Autofluorescent imaging and target ablation

ABSTRACT

Apparatus, devices, methods, systems, computer programs and computing devices related to autofluorescent imaging and ablation are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to and claims the benefit of theearliest available effective filing date(s) from the following listedapplication(s) (the “Related Applications”) (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC § 119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Related Application(s)).

RELATED APPLICATIONS

-   -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 11/403,230, entitled        LUMENALLY-ACTIVE DEVICE, naming Bran Ferren; W. Daniel Hillis;        Roderick A. Hyde; Muriel Y Ishikawa; Edward K. Y. Jung;        Nathan P. Myhrvold; Elizabeth A. Sweeney; Clarence T. Tegreene;        Richa Wilson; Lowell L. Wood, Jr. and Victoria Y. H. Wood as        inventors, filed 12 Apr. 2006, which is currently co-pending, or        is an application of which a currently co-pending application is        entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 11/645,357, entitled        LUMENALLY-TRAVELING DEVICE, naming Bran Ferren; W. Daniel        Hillis; Roderick A. Hyde; Muriel Y Ishikawa; Edward K. Y. Jung;        Eric C. Leuthardt; Nathan P. Myhrvold; Elizabeth A. Sweeney;        Clarence T. Tegreene; Richa Wilson; Lowell L. Wood, Jr. and        Victoria Y. H. Wood as inventors, filed 21 Dec. 2006, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. [To Be Assigned], entitled        AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming Edward S.        Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C. Leuthardt;        Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L. Wood, Jr. as        inventors, filed 24 Aug. 2007, which is currently co-pending, or        is an application of which a currently co-pending application is        entitled to the benefit of the filing date. [Attorney Docket No.        0606-002-012A-000000]    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. [To Be Assigned], entitled SYSTEMS        FOR AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming        Edward S. Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C.        Leuthardt; Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L.        Wood, Jr. as inventors, filed 24 Aug. 2007, which is currently        co-pending, or is an application of which a currently co-pending        application is entitled to the benefit of the filing date.        [Attorney Docket No. 0606-002-012B-000000]    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. [To Be Assigned], entitled SYSTEMS        FOR AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming        Edward S. Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C.        Leuthardt; Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L.        Wood, Jr. as inventors, filed 24 Aug. 2007, which is currently        co-pending, or is an application of which a currently co-pending        application is entitled to the benefit of the filing date.        [Attorney Docket No. 0606-002-012C-000000]    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. [To Be Assigned], entitled        AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming Edward S.        Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C. Leuthardt;        Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L. Wood, Jr. as        inventors, filed 24 Aug. 2007, which is currently co-pending, or        is an application of which a currently co-pending application is        entitled to the benefit of the filing date. [Attorney Docket No.        0606-002-012D-000000]    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of United        States Patent Application No. [To Be Assigned], entitled SYSTEM        FOR AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming        Edward S. Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C.        Leuthardt; Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L.        Wood, Jr. as inventors, filed 24 Aug. 2007, which is currently        co-pending, or is an application of which a currently co-pending        application is entitled to the benefit of the filing date.        [Attorney Docket No. 0606-002-012E-000000]    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. [To Be Assigned], entitled        AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming Edward S.        Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C. Leuthardt;        Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L. Wood, Jr. as        inventors, filed 24 Aug. 2007, which is currently co-pending, or        is an application of which a currently co-pending application is        entitled to the benefit of the filing date. [Attorney Docket No.        0606-002-012G-000000]    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. [To Be Assigned], entitled        AUTOFLUORESCENT IMAGING AND TARGET ABLATION, naming Edward S.        Boyden; Roderick A. Hyde; Muriel Y. Ishikawa; Eric C. Leuthardt;        Nathan P. Myhrvold; Dennis J. Rivet; and Lowell L. Wood, Jr. as        inventors, filed 24 Aug. 2007, which is currently co-pending, or        is an application of which a currently co-pending application is        entitled to the benefit of the filing date. [Attorney Docket No.        0606-002-012H-000000]

The United States Patent Office (USPTO) has published a notice to theeffect that the USPTO's computer programs require that patent applicantsreference both a serial number and indicate whether an application is acontinuation or continuation-in-part. Stephen G. Kunin, Benefit ofPrior-Filed Application, USPTO Official Gazette Mar. 18, 2003, availableat http://www.uspto.gov/web/offices/com/sol/og/2003/week11/patbene.htm.The present Applicant Entity (hereinafter “Applicant”) has providedabove a specific reference to the application(s) from which priority isbeing claimed as recited by statute. Applicant understands that thestatute is unambiguous in its specific reference language and does notrequire either a serial number or any characterization, such as“continuation” or “continuation-in-part,” for claiming priority to U.S.patent applications. Notwithstanding the foregoing, Applicantunderstands that the USPTO's computer programs have certain data entryrequirements, and hence Applicant is designating the present applicationas a continuation-in-part of its parent applications as set forth above,but expressly points out that such designations are not to be construedin any way as any type of commentary and/or admission as to whether ornot the present application contains any new matter in addition to thematter of its parent application(s).

All subject matter of the Related Applications and of any and allparent, grandparent, great-grandparent, etc. applications of the RelatedApplications is incorporated herein by reference to the extent suchsubject matter is not inconsistent herewith.

SUMMARY

The present application relates, in general, to apparatus and devicesfor fluorescent-based imaging and ablation of medical targets, as wellas related methods and systems implementations. Such apparatus, devices,methods and/or systems are useful for ablating target cells and/ortissues as well as treatment, prevention, and/or amelioration of avariety of diseases and disorders. Apparatus and/or devices may beconfigured to be used externally or internally, to be handheld,intra-luminal, or ingestible, and/or to be tethered or untethered.Various methods and/or systems implementations include using one or moreof the apparatus or devices for ablating target cells in wounds and/orsurgical lesions, intra-lumenally, or in the digestive tract.Illustrative examples include using one or more of the apparatus,devices, methods and/or systems to treat H. pylori infection, and/or totest and ablate cancer margins.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic of an illustrative apparatus in whichembodiments may be implemented.

FIG. 2 shows a schematic of illustrative embodiments of the apparatus ofFIG. 1, with illustrative examples of an energy source.

FIG. 3 shows a schematic of illustrative embodiments of the apparatus ofFIG. 1, with illustrative examples of a sensor.

FIGS. 4-6 show a schematic of an illustrative untethered device in whichembodiments may be implemented.

FIG. 7 shows a schematic of an illustrative tethered device in whichembodiments may be implemented.

FIG. 8 and FIG. 9 show an operational flow representing illustrativeembodiments of operations related to providing a first output to a firstenergy source in real time, the first output providing data associatedwith at least partial ablation of a target at least partially based onthe first possible dataset.

FIG. 10 and FIG. 11 show an operational flow representing illustrativeembodiments of operations related to providing a first output to a firstenergy source in real time, the first output providing datarepresentative of one or more ablation characteristics for at leastpartially ablating a target area.

FIG. 12 and FIG. 13 show an operational flow representing illustrativeembodiments of operations related to providing a first possible outputto a first motive source, the first possible output providing datarepresentative of one or more parameters associated with movement of anuntethered device in a lumen at least partially based on the location ofthe target area.

FIGS. 14-19 show a partial view of an illustrative embodiment of acomputer program product that includes a computer program for executinga computer process on a computing device.

FIGS. 20-25 show an illustrative embodiment of a system in whichembodiments may be implemented.

FIG. 26 shows a schematic of an example of an illustrative embodiment ofa handheld device in use on an illustrative subject.

FIG. 27 shows a schematic of an example of an illustrative embodiment ofa device in use on an illustrative subject.

FIG. 28 shows a schematic of an example of an illustrative embodiment ofa handheld device in use on an illustrative subject.

FIG. 29 shows a schematic of an example of an illustrative embodiment ofa device in use on an illustrative subject.

FIGS. 30-31 show a schematic of an example of an illustrative embodimentof a handheld device.

FIGS. 32A, 32B, and 32C show a schematic of an example of anillustrative embodiment of a handheld device.

FIG. 33 shows a schematic of an example of an illustrative embodiment ofan untethered device in use on an illustrative subject.

FIGS. 34-40 show a schematic of an example of an illustrative embodimentof an untethered device in use on an illustrative subject.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

The present application relates, in general, to apparatus, devices,systems, and methods of fluorescent imaging, optionally autofluorescentimaging, and ablation of medical targets. Those having skill in the artwill appreciate that the specific systems, apparatus, devices, andmethods described herein are intended as merely illustrative of theirmore general counterparts.

In one aspect, FIG. 1 through FIG. 7 depict one or more embodiments ofone or more apparatus 100 and/or 500 and/or devices 200, 300, and/or 400configured to detect and ablate targets at least partially based on afluorescent response. Although one or more embodiments of one or moreapparatus and/or devices may be presented separately herein, it isintended and envisioned that one or more apparatus and/or devices and/orembodiments of one or more apparatus and/or devices, in whole or inpart, may be combined and/or substituted to encompass a full disclosureof the one or more apparatus and/or devices. In some embodiments, one ormore apparatus and/or devices may include one or more systemimplementations including methods of operations, and/or include one ormore computing devices and/or systems configured to perform one or moremethods. As disclosed below, one or more apparatus and/or devices may beused in one or more methods of treatment and/or methods for ablatingtargets described herein.

FIG. 1, FIG. 2, and FIG. 3 depict illustrative embodiments of one ormore apparatus 100 having a first energy source 110 alignable to alesion and configured to provide electromagnetic energy selected toinduce a fluorescent response from a target area in the lesion; a sensor120 configured to detect the fluorescent response; control circuitry 130coupled to the sensor 120 and responsive to identify the target area;and a second energy source 110 responsive to the control circuitry 130and configured to emit energy selected to at least partially ablate thetarget area.

FIG. 4, FIG. 5, and FIG. 6 depict illustrative embodiments of one ormore untethered device 200, 300, and 400, respectively.

FIG. 4 depicts illustrative embodiments of one or more untethered device200 having an energy source 100, optionally a first electromagneticenergy source 111 configured to function in a lumen and configured toprovide electromagnetic energy selected to induce an auto-fluorescentresponse in one or more target cells in proximity to the lumen; a sensor120 configured to detect the auto-fluorescent response; controlcircuitry 130 coupled to the sensor 120 and responsive to identify atarget area; optionally a second electromagnetic energy source 111responsive to the control circuitry 130 and configured to emit energyselected to at least partially ablate the target area, optionally apower source 140, and optionally a motive source 150.

FIG. 5 depicts illustrative embodiments of one or more devices 300 fortreating or ameliorating H. pylori infection including an untetheredingestible mass 310 optionally shaped for non-uniform movement having anelectromagnetic energy source 111 optionally configured to emit variabledirectional electromagnetic energy in a manner selected to inducephotodynamic cell death in H. pylori 4. In some embodiments, one or moredevices 300 for ablating H. pylori include an untethered ingestible mass310, optionally shaped for non-uniform movement, having anelectromagnetic energy source 111 optionally configured to emit variabledirectional electromagnetic energy in a manner selected to inducephotodynamic cell death in H. pylori.

FIG. 6 depicts illustrative embodiments of one or more devices 400including an untethered ingestible mass 310 optionally configured torotate, optionally shaped for non-uniform movement, wherein theuntethered ingestible mass 310 includes: an energy source 110,optionally a first electromagnetic energy source 111 configured toprovide electromagnetic energy selected to stimulate an auto-fluorescentresponse in one or more target cells in a digestive tract; a sensor 120configured to detect the auto-fluorescent response; control circuitry130 coupled to the sensor 120 and responsive to identify a target area;optionally a second electromagnetic energy source 111 responsive to thecontrol circuitry 130 and configured to emit energy selected to at leastpartially ablate the target area, optionally a power source 140, andoptionally a motive source 150.

FIG. 7 depicts illustrative embodiments of one or more tethered 510apparatus 500 including a first energy source 110 configured to provideelectromagnetic energy selected to stimulate an auto-fluorescentresponse in one or more target cells in an internal location; a sensor120 configured to detect the auto-fluorescent response; controlcircuitry 130 coupled to the sensor 120 and responsive to identify atarget area in real time; and optionally a second energy source 110responsive to the control circuitry 130 and configured to emit energyselected to at least partially ablate the target area.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may be configured for use in one or more lesions,lumens, and/or internal locations of an organism. In illustrativeembodiments, one or more apparatus 100, in part or in whole, isoptionally a handheld device configured for detecting and ablatingmicrobial and/or pathological contamination or cancer cells, forexample, in lesions, optionally wounds or surgical incisions. Inillustrative embodiments, one or more devices 200, in part or in whole,is an intra-lumenally sized device (e.g. small enough to be placed in ablood vessel while not obstructing the flow) configured for detectingand ablating microbial and/or pathogenic infections or cancercells/metastases, for example, in the blood stream. In illustrativeembodiments, one or more devices 300 and/or 400, in whole or in part, isan ingestibly-sized device (e.g. the size of a large vitamin pill)configured for detecting and ablating microbial and/or pathogenicinfections or cancer cells, for example, in the digestive tract. Inillustrative embodiments, one or more apparatus 500, in whole or inpart, is part of or attached to a device, optionally handheld (e.g. anendoscope or fiber optic cable) and configured for detecting andablating microbial and/or pathogenic infections or cancer cells, forexample, in internal locations.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may be configured as a self-contained unit that includesall functionalities necessary for operation of the device and/orapparatus, or configured as one or more subparts in one or morelocations separate from one another, wherein one or more of the subpartsincludes one or more essential and/or non-essential functionalities. Inillustrative examples, one subpart may be placed within a lumen of, forexample, a blood vessel, and another subpart placed, for example,sub-cutaneously or within a larger or more accessible lumen. Inillustrative embodiments, a remote portion may provide for monitoring ofthe lumen-based device or data collection or analysis. The remoteportion may be at a separate location within the body of the subject, oroutside the body of the subject. Data and/or power signals may betransmitted between the one or more subparts using electromagneticsignals, for example, or electrical or optical links. Methods ofdistributing functionalities of a system between hardware, firmware, andsoftware at located at two or more sites are well known to those ofskill in the art.

Embodiments of one or more apparatus 100 and/or 500 may be configured asa handheld unit, optionally self-contained and/or with one or moresubparts in one or more other locations. In illustrative embodiments, ahand held unit includes one or more sources of energy 110, and at leastone monitor to provide viewing of the lesion and targetingelectromagnetic energy 118. In illustrative embodiments, a hand heldunit includes control circuitry and at least one monitor for viewinglesion targeting information, as well as being connected to an energysource 110 and optionally one or more power sources 140 through one ormore conduits. In illustrative embodiments, a handheld unit iswirelessly connected to control circuitry and to a monitor providingtargeting information to an operator. In illustrative embodiments,apparatus 100 is a mounted, non-handheld, unit.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may be described as having one or more subpartsincluding, but not limited to, one or more energy sources 110, one ormore sensors 120, one or more control circuitry 130, one or more powersources 140, and/or one or more motive sources 150. In some embodiments,one or more subpart may be a physically distinct unit. In someembodiments, one or more subpart is combined with one or more othersubpart to form a single unit with no physically discernible separation.Some embodiments include a first, second, third, fourth, fifth, etc.energy source 110, sensor 120, control circuitry 130, power source 140,and/or motive source 150. One or more of the one, two three, four, five,etc. components may be the same component and/or physical entity, or oneor more components may be a separate physical entity. For example, theremay be two lasers in a device, or there may be one laser able to provideboth excitation and ablation energy. For example, there may be twosensors in a device, or there may be one sensor able to detect a varietyof energy wavelengths.

As used herein, the term “lesion” may include wounds, incisions, and/orsurgical margins. In some embodiments, the term “lesion” may include,but is not limited to, cells and/or tissues, optionally including cellsand/or tissues of the skin and/or retina. Wounds may include, but arenot limited to, scrapes, abrasions, cuts, tears, breaks, punctures,gashes, slices, and/or any injury resulting in bleeding and/or skintrauma sufficient for foreign organisms to penetrate. Incisions mayinclude those made by a medical professional, such as but not limitedto, physicians, nurses, mid-wives, and/or nurse practitioners, dentalprofessionals, such as but not limited to, dentists, orthodontists,dental hygienists, and veterinary professionals, including but notlimited to, veterinarians during treatment optionally including surgery.As used herein, the term “surgical margins” may include the edges ofincisions, for example, cancer margins.

As used herein, the term “lumen” may include, but is not limited to,part or all of a nostril or nasal cavity, the respiratory tract, thecardiovascular system (e.g., a blood vessel, including for example,arteries, veins, and capillaries), the lymphatic system, the biliarytract, the urogenital tract (e.g. a ureter), the oral cavity, thedigestive tract, the tear ducts, a glandular system, a male or femalereproductive tract (e.g. fallopian tubes, uterus, the epididymis, vasdeferens, ductal deferens, efferent duct, ampulla, seminal duct,ejaculatory duct, and/or urethra), the cerebral-spinal fluid space (e.g.the cerebral ventricles, the subarachnoid space, and/or the spinalcanal), the thoracic cavity, the abdominal cavity, and otherfluid-containing structures of an organism. Other lumens may be found inthe auditory or visual system, or in interconnections thereof, e.g., theEustachian tubes.

Also included within the scope of the term “lumen” are man-made lumenswithin the body, including vascular catheters, spinal fluid shunts,vascular grafts, bowel re-anastomoses, bypass grafts, indwelling stentsof various types (e.g., vascular, gastrointestinal, tracheal,respiratory, urethral, genitourinary, etc.) and surgically createdfistulas. Other man-made lumens may be found associated with one or moreimplants, such as but not limited to, partial and/or complete jointreplacements (knee, hip, shoulder, ankle, etc.) and/or partial and/orcomplete bone replacements (spinal vertebra, femur, shin, etc.).

As used herein, the term “internal location” may include locationswithin the body of a subject appropriate for the placement of one ormore device and/or apparatus. Internal locations may be natural and/orman-made. In illustrative embodiments, one or more devices and/orsubparts may be associated with one or more manmade objects within asubject, such as but not limited to, one or more stents, screws, rods,artificial joints, etc. Such internal locations are known to those withskill in the art and/or described herein.

As used herein, the term “in proximity to” may include, but is notlimited to, a space and/or area near to a defined area, such as alesion, lumen and/or internal location. Locations that are in proximityto a lumen may include, for example, locations internal to the lumen,parts, or all, of the width of the lumen wall, and locations external tothe lumen wall. In some embodiments, “in proximity to” may includedistances such as, but not limited to, approximately 0.1, 1.0, 10,and/or 100 μms and/or 0.1, 1.0, 10, and/or 100 mms, and may optionallyinclude larger and/or smaller distances depending on the energy provided(e.g. electromagnetic energy, particle beam, two-photon, pulsed, etc.)and/or the sensitivity of detection. Those of skill in the art wouldknow (and/or are able to calculate) the applicable distance for eachform of energy.

As used herein, the term “subject” may include, but is not limited to,one or more living entities including, but not limited to, animals,mammals, humans, reptiles, birds, amphibians, and/or fish. The animalsmay include, but are not limited to, domesticated, wild, research, zoo,sports, pet, primate, marine, and/or farm animals. Animals include, butare not limited to, bovine, porcine, swine, ovine, murine, canine,avian, feline, equine, and/or rodent animals. Domesticated and/or farmanimals include, but are not limited to, chickens, horses, cattle, pigs,sheep, donkeys, mules, rabbits, goats, ducks, geese, chickens, and/orturkeys. Wild animals include, but are not limited to, non-humanprimates, bear, deer, elk, raccoons, squirrels, wolves, coyotes,opossums, foxes, skunks, and/or cougars. Research animals include, butare not limited to, rats, mice, hamsters, guinea pigs, rabbits, pigs,dogs, cats and/or non-human primates. Pets include, but are not limitedto, dogs, cats, gerbils, hamsters, guinea pigs and/or rabbits. Reptilesinclude, but are not limited to, snakes, lizards, alligators,crocodiles, iguanas, and/or turtles. Avian animals include, but are notlimited to, chickens, ducks, geese, owls, sea gulls, eagles, hawks,and/or falcons. Fish include, but are not limited to, farm-raised, wild,pelagic, coastal, sport, commercial, fresh water, salt water, and/ortropical. Marine animals include, but are not limited to, whales,sharks, seals, sea lions, walruses, penguins, dolphins, and/or fish.

The dimensions and mechanical properties (e.g., rigidity) of the one ormore apparatus 500 and/or devices 200, 300, and/or 400, and particularlyof the structural elements of the one or more apparatus and/or device,may be selected for compatibility with the location of use in order toprovide for reliable positioning and/or to provide for movement of theapparatus and/or device while preventing damage to the lesion, lumen,and/or internal location and its surrounding structure. In illustrativeembodiments, an apparatus and/or device may be internal or external,tethered or untethered, motile or immobile, and/or optionallyingestible.

The choice of structural element size and configuration appropriate fora particular body lumen and/or internal location may be selected by aperson of skill in the art. Structural elements may be constructed usinga variety of manufacturing methods, from a variety of materials.Appropriate materials may include metals, ceramics, polymers, andcomposite materials having suitable biocompatibility, sterilizability,mechanical, and physical properties, as will be known to those of skillin the art. Examples of materials and selection criteria are described,for example, in The Biomedical Engineering Handbook (Second Edition,Volume I, J. D. Bronzino, Ed., Copyright 2000, CRC Press LLC, pp.IV-1-43-31). Manufacturing techniques may include injection molding,extrusion, die-cutting, rapid-prototyping, etc., and will depend on thechoice of material and device size and configuration. Sensing andenergy-emitting portions of the devices as well as associated controlcircuitry may be fabricated on the structural elements using variousmicrofabrication and/or MEMS techniques (see, e.g., U.S. PatentApplications 2005/0221529, 2005/0121411, 2005/0126916, and Nyitrai, etal. “Preparing Stents with Masking & Etching Technology” (2003) 26^(th)International Spring Seminar on Electronics Technology pp. 321-324,IEEE), or may be constructed separately and subsequently assembled tothe structural elements, as one or more distinct components. See also,U.S. patent application Ser. Nos. 11/403,230 and 11/645,357.

The choice of structural element size and configuration appropriate fora motile, optionally affixable, device may be selected by a person ofskill in the art. Configurations for structural elements of motiledevices include, but are not limited to, a substantially tubularstructure, one or more lumens in fluid communication with the bodylumen, and/or an adjustable diameter (see, e.g., U.S. patent applicationSer. Nos. 11/403,230 and 11/645,357). Structural elements may have theform, for example, of a short cylinder, an annulus, a cylinder, and/or aspiral. A spiral structure is disclosed, for example, in Bezrouk et al,(“Temperature Characteristics of Nitinol Spiral Stents” (2005) ScriptaMedica (BRNO) 78(4):219-226. Elongated forms such as cylinders orspirals may be suitable for use in tubular lumen-containing structuressuch as, for example, blood vessels.

In additional to materials disclosed above, flexible material havingadjustable diameter, taper, and length properties may be used as part ofthe structural material. For example, some materials may change from alonger, narrower configuration, to a shorter, wider configuration, ormay taper over their length. Structural elements that may exhibit thistype of expansion/contraction property may include mesh structuresformed of various metals or plastics, and some polymeric materials, forexample (see, e.g., “Agile new plastics change shape with heat” MIT NewsOffice (Nov. 20, 2006) pp. 1-4; MIT Tech Talk (Nov. 22, 2006) p. 5;http://web.mit.edu/newsoffice/2006/triple-shape.html; and Shanpoor etal., Smart Materials and Structures (2005) 14:197-214, Institute ofPhysics Publishing).

In some embodiments, the structural element may include a self-expandingmaterial, a resilient material, or a mesh-like material. Flexibility mayalso be conferred by configuration as well as material; the structuralelement may include a slotted structure and/or mesh-like material, forexample. Structural elements may be formed from various materials,including metals, polymers, fabrics, and various composite materials,including ones of either inorganic or organic character, the latterincluding materials of both biologic and abiologic origin, selected toprovide suitable biocompatibility and mechanical properties. Thestructural element may include a biocompatible material, and may includea bioactive component (such as a drug releasing coating or bioactivematerial attached to or incorporated into the structural element).

It is contemplated that additional components, such as energy sources110, sensors 120, control circuitry 130, power sources 140, and/ormotive sources 150 (e.g. propelling mechanisms), for example, will beattached, connected to, place within, manufactured on or in, and/orformed integrally with the structural element. Methods for manufactureand/or assembly are known in the art and/or described herein.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may include one or more energy sources 110. One or moreenergy sources 110 may include, but are not limited to, one or moreelectromagnetic energy sources 111 and/or one or more charged particleenergy sources 112. One or more electromagnetic energy sources 111 mayinclude, but are not limited to, one or more optical energy sources 113and/or one or more X-ray energy sources 115. One or more optical energysources 113 may include, but are not limited to, one or more visualenergy sources 114. In some embodiments one or more electromagneticenergy source 111 is a laser.

In some embodiments, one or more apparatus 100 and/or 500 is, in wholeor in part, handheld. In some embodiments one or more energy source 110,optionally one or more electromagnetic energy source 111, is handheld.In some embodiments one or more energy source 110, optionally one ormore electromagnetic energy source 111, is in the same handheld unit. Insome embodiments one or more energy source 110, optionally one or moreelectromagnetic energy source 111, is in a different handheld unit.

In some embodiments, one or more energy sources 110 optionally provideenergy for excitation of a fluorescent response 116, energy fortargeting 118, and/or energy for ablation 117 of one or more targets. Insome embodiments, one energy source 110 provides excitation energy 116,targeting energy 118, and ablation energy 117. In some embodiments,different energy sources 110 provide excitation energy 116, targetingenergy 118, and ablation energy 117. In some embodiments, one energysource 110 provides excitation energy 116 and ablation energy 117, andoptionally targeting energy 118. In some embodiments, more than oneenergy source 110 provides excitation energy 116. In some embodiments,more than one energy source provides ablation energy 117.

In some embodiments, one or more electromagnetic energy sources 111provide one or more of excitation energy 116, ablation energy 117,and/or targeting energy 118. In some embodiments, one or more opticalenergy sources 113 (optionally visual energy sources 114) provide one ormore of excitation energy 116, ablation energy 117, and/or targetingenergy 118. In some embodiments, one or more X-ray energy sources 115provide ablation energy. In some embodiments, one or more particle beamsources 112 provide ablation energy.

In some embodiments, one or more energy sources 110 are programmable,remote-controlled, wirelessly controlled, and or feedback-controlled.

As used herein, the term “electromagnetic energy” may include radiowaves, microwaves, tetrahertz radiation, infrared radiation, visiblelight, X-rays, and gamma rays. In some embodiments, one or more of thesefrequencies may be explicitly excluded from the general category ofelectromagnetic energy (e.g. electromagnetic energy sources, but notincluding X-ray energy sources). Electromagnetic energy (or radiation)with a wavelength between approximately 400 nm and 700 nm is detected bythe human eye and perceived as visible light. Optical light may alsoinclude near infrared (longer than 700 nm) and ultraviolet (shorter than400 nm). In illustrative embodiments, electromagnetic energy isgenerated at one or more wavelengths of approximately 100-280 nm,180-350 nm, 200-340 nm, 250-400 nm, 250-450 nm, 280-315 nm, 280-540 nm,300-460 nm, 300-600 nm, 300-700 nm, 310-510 nm, 315-400 nm, 350-390 nm,350-700 nm, 360-370 nm, 360-600 nm, 375-425 nm, 375-440 nm, 400-1000 nm,407-420 nm, 410-430 nm, 445-470 nm, 450-490 nm, 450-560 nm, 455-490 nm,465-495 nm, 490-690 nm, 505-550 nm, 515-555 nm, 580-600 nm, 600-1600 nm,250 nm, 265 nm, 290 nm, 330 nm, 335 nm, 337 nm, 340 nm, 350 nm, 352 nm,360 nm, 365 nm, 385 nm, 395 nm, 400 nm, 405 nm, 410 nm, 420 nm, 430 nm,435 nm, 436 nm, 440 nm, 444 nm, 450 nm, 455 nm, 460 nm, 465 nm, 469 nm,470 nm, 480 nm, 481 nm, 483 nm, 485 nm, 486 nm, 487 nm, 488 nm, 490 nm,495 nm, 500 nm, 506 nm, 514 nm, 516 nm, 520 nm, 530 nm, 538 nm, 545 nm,546 nm, 550 nm, 560 nm, 570 nm, 581 nm, 585 nm, 600 nm, 609 nm, 610 nm,620 nm, 630 nm, 632 nm, 635 nm, 636 nm, 640 nm, 644 nm, 665 nm, 670 nm,700 nm, 880 nm, 950 nm, 1064 nm, 1320 nm, 2070 nm, and/or 2940 nm, amongothers.

As used herein, the term “charged particle” may include particlesgenerated using one or more particle beams. A particle beam isoptionally an accelerated stream of charged particles or atoms that maybe directed by magnets and focused by electrostatic lenses, althoughthey may also be self-focusing. Particle beams may be high energy beams(e.g. created in particle accelerators), medium and/or low energy beams.

Electromagnetic or optical energy is made up of photons. Electromagneticenergy includes, but is not limited to, single photon electromagneticenergy, two photon electromagnetic energy, multiple wavelengthelectromagnetic energy, and extended-spectrum electromagnetic energy.Electromagnetic energy may be used for excitation of fluorescence,targeting, and/or for ablation of one or more targets. As used herein,the term “fluorescence” may include the production of light (emission)following excitation by electromagnetic energy. Fluorescence may resultfrom emissions from exogenously provided tags and/or markers, and/or aninherent response of one or more targets to excitation withelectromagnetic energy. As used herein, the term “auto-fluorescence” mayinclude an inherent fluorescent response from one or more targets.

Electromagnetic energy sources 111 may be configured to emit energy as acontinuous beam or as a train of short pulses. In the continuous wavemode of operation, the output is relatively consistent with respect totime. In the pulsed mode of operation, the output varies with respect totime, optionally having alternating ‘on’ and off periods. Inillustrative examples, one or more energy sources are configured to emitpulsed energy to specifically ablate a limited area and/or a limitednumber of target cells. In illustrative examples, one or more energysources are configured to emit continuous energy to excite endogenousfluorophores to emit fluorescence.

One or more electromagnetic energy sources 111 may include one or morelasers having one or more of a continuous or pulsed mode of action. Oneor more pulsed lasers may include, but are not limited to, Q-switchedlasers, mode locking lasers, and pulsed-pumping lasers. Mode lockedlasers emit extremely short pulses on the order of tens of picosecondsdown to less than 10 femtoseconds, the pulses optionally separated bythe time that a pulse takes to complete one round trip in the resonatorcavity. Due to the Fourier limit, a pulse of such short temporal lengthmay have a spectrum which contains a wide range of wavelengths.

In some embodiments, the electromagnetic energy is focused at a depth ofapproximately 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm,0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm,1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm,2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, or 3.0 mm below the surface of thelesion, beyond the surface of a wall of the lumen, and/or beyond asurface of an internal location. In some embodiments, theelectromagnetic energy is focused at a depth of approximately 0.1 to 3mm, 0.1 to 2.5 mm, 0.1 to 2.0 mm, 0.1 to 1.5 mm, 0.1 to 1.0 mm, 0.1 to0.5 mm, 0.5 to 3.0 mm, 0.5 to 2.5 mm, 0.5 to 2.0 mm, 0.5 to 1.5 mm, 0.5to 1.0 mm, 1.0 to 3.0 mm, 1.0 to 2.5 mm, 1.0 to 2.0 mm, 1.0 to 1.5 mm,1.5 to 3.0 mm, 1.5 to 2.5 mm, 1.5 to 2.0 mm, 2.0 to 3.0 mm, 2.0 to 2.5mm, or 2.5 to 3.0 mm below the surface of the lesion, beyond the surfaceof a wall of the lumen, and/or beyond a surface of an internal location.

In some embodiments, the electromagnetic energy is generated by twophotons having the same wavelength. In some embodiments, theelectromagnetic energy is generated by two photons having a differentwavelength. Electromagnetic energy generated by two photons isoptionally focused at a depth below the surface of the lesion, beyondthe surface of a wall of the lumen, and/or beyond a surface of aninternal location, optionally at one or more depths as described aboveand/or herein.

As used herein, the term “two-photon” may include excitation of afluorophore by two photons in a quantum event, resulting in the emissionof a fluorescence photon, optionally at a higher energy than either ofthe two excitatory photons, optionally using a femtosecond laser. Insome embodiments, two photon electromagnetic energy is coupled through avirtual energy level and/or coupled through an intermediate energylevel.

As used herein, the term “extended-spectrum” may include a range ofpossible electromagnetic radiation wavelengths within the full spectrumof possible wavelengths, optionally from extremely long to extremelyshort. One of skill in the art is able to select appropriate ranges forthe devices and methods disclosed herein based on information publiclyavailable and/or disclosed herein.

In some embodiments, the electromagnetic energy may be defined spatiallyand/or directionally. In some embodiments, the electromagnetic energymay be spatially limited, optionally spatially focused and/or spatiallycollimated. In illustrative embodiments, the electromagnetic energyoptionally contacts less than less than an entire possible area, or anentire possible target, and/or is limited to a certain depth within atissue.

In some embodiments, the electromagnetic energy may be directionallylimited, directionally varied, and/or directionally variable. Inillustrative embodiments, the electromagnetic energy may be providedonly in a single direction, for example 90 degrees from the horizontalaxis of a device, or toward a lumen wall, a lesion, or an internallocation. In illustrative embodiments, the electromagnetic energy may beprovided over a range of directions for example, through movement of theelectromagnetic source, through movement of the entire device (e.g.rotation, random movement, wobbling, tumbling), and/or throughillumination from a variety of sources in the device.

Electromagnetic energy configured to induce a fluorescent response in atarget may be selected, optionally manually, remotely, programmably,wirelessly, and/or using feedback information. Frequencies that induce afluorescent response in one or more targets are known in the art and/ordiscussed herein. In some embodiments, selection of excitation energy116 may be performed in advance, or as a result of information received,optionally including feedback information, optionally from one or moresensors 120.

Electromagnetic energy and/or particle beam energy configured to ablateone or more targets may be selected, optionally manually, remotely,programmably, wirelessly, and/or using feedback information. Frequenciesuseful to at least partially ablate one or more targets are known in theart and/or discussed herein. In some embodiments, selection of ablationenergy 117 may be performed in advance, or as a result of informationreceived, optionally including feedback information, optionally from oneor more sensors 120.

In addition to electromagnetic energy described herein, the ablationenergy may be supplied by energetic charged particles, such aselectrons, protons, or other ions. In one embodiment, the chargedparticles are directed towards the autofluorescent target in the form ofparticle beams. In another embodiment, the charged particles are emittedover relatively wide solid-angles, and address the designatedautofluorescent target by virtue of spatial proximity.

In one embodiment, particle beams are generated outside the body by beamgenerators such as particle accelerators, cathode ray tubes,electrostatic accelerators, voltage-multiplier accelerators,Cockcroft-Walton accelerators, Van de Graaff accelerators, Alvarezaccelerators, linear accelerators, circular accelerators, wakefieldaccelerators, collimated radioactive emitters, etc. The beams from thesesources can be directed towards the autofluorescent target bymechanical, electrical, or magnetic methods. In some embodiments, theparticle beams may be generated and directed from locations separatefrom the light source used to induce the autofluorescent response. Inother embodiments, the particle beam may be generated in proximity tothe autofluorescence inducing light source, by using compact particlesources such as electrostatic accelerators, Alvarez accelerators, linearaccelerators, voltage-multiplier accelerators, Cockcroft-Waltonaccelerators, wakefield accelerators, collimated radioactive emitters,etc.

In some embodiments, particle beams are generated and delivered frominside the body. Compact particle beam generators such as electrostaticaccelerators, Alvarez accelerators, linear accelerators,voltage-multiplier accelerators, Cockcroft-Walton accelerators, orwakefield accelerators can be used. In one embodiment of avoltage-multiplier accelerator, the staged voltage elements can usehigh-field-strength capacitors. In another embodiment, the stagedvoltages can be generated in an array of photocells by photogenerationusing on-board or off-board light sources. In another embodiment of anin-vivo particle source, a radioactive emitter can be used to provide acharged particle source. One example of such a source is the Beta-Cath™System, developed by Novoste Corp.

In one embodiment, in-vivo radioactive sources can be encapsulatedwithin shielding which can be used to control charged particle exposureto nearby tissue. The shielding can have one or more portals, allowingfor collimated emission. The shielding can be movable, either across allor part of its extent, or across one or more portal openings, in orderto provide switchable particle sources. Shielding can be controllablymoved by mechanical techniques such as valves, shutters, or similardevices, can utilize movable liquids, such as Hg, or utilize othermethods. The particles from these in-vivo sources can be directedtowards the autofluorescent target by mechanical, electrical, ormagnetic methods, or may rely upon proximity.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may include one or more targeting electromagnetic energysources 118. Targeting electromagnetic energy is optionally from one ormore optical energy sources 113, optionally from one or more visiblelight sources 114. In some embodiments, the one or more targeting energysource 118 is aligned with the excitation energy source 116 and/or theablation energy source 117. In illustrative embodiments, the targetingenergy source 118 provides a visual indication of the directionalalignment of the excitation energy 116 to induce a fluorescent response,and/or the ablation energy 117 to at least partially ablate one or moretargets.

In some embodiments, the one or more targeting energy source 118 has thesame spatial extent as the excitation energy 116 and/or the ablationenergy 117. In some embodiments, the one or more targeting energy source118 has a different spatial extent than the excitation energy 116 and/orthe ablation energy 117. In illustrative embodiments, the targetingenergy is a visually detectable beam of light that is narrower than theexcitation energy and/or ablation energy beam. In illustrativeembodiments, the targeting energy is a visually detectable beam of lightthat is focused at the midpoint of the excitation and/or ablation energybeam. In illustrative embodiments, the targeting energy is a visuallydetectable beam of light that is broader than the excitation and/orablation energy beam.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may include one or more sensors 120. In someembodiments, one or more sensors 120 are the same sensor. In someembodiments, one or more sensors 120 are different sensors. In someembodiments, one or more sensors are in the same unit, optionally ahandheld unit. In some embodiments, one or more sensors 120 are inseparate units. In some embodiments, one or more sensors 120 are in thesame and/or different units than one or more energy sources 110.

The one or more sensors may include, but are not limited to,electromagnetic energy detectors 121 (e.g. optical energy such as nearIR, UV, visual), pH detectors 122, chemical and biological moleculedetectors 123 (e.g. blood chemistry, chemical concentration,biosensors), physiological detectors 124 (e.g. blood pressure, pulse,peristaltic action, pressure sensors, flow sensors, viscosity sensors,shear sensors), time detectors 125 (e.g. timers, clocks), imagingdetectors 126, acoustic sensors 127, temperature sensors 128, and/orelectrical sensors 129. One or more sensors may be configured to measurevarious parameters, including, but not limited to, the electricalresistivity of the fluid, the density or sound speed of the fluid, thepH, the osmolality, or the index of refraction of the fluid at least onewavelength. The selection of a suitable sensor for a particularapplication or use site is considered to be within the capability of aperson having skill in the art. One or more of these and/or othersensing capabilities may be present in a single sensor or an array ofsensors; sensing capabilities are not limited to a particular number ortype of sensors.

One or more biosensors 123 may detect materials including, but notlimited to, a biological marker, an antibody, an antigen, a peptide, apolypeptide, a protein, a complex, a nucleic acid, a cell (and, in somecases, a cell of a particular type, e.g. by methods used in flowcytometry), a cellular component, an organelle, a gamete, a pathogen, alipid, a lipoprotein, an alcohol, an acid, an ion, an immunomodulator, asterol, a carbohydrate, a polysaccharide, a glycoprotein, a metal, anelectrolyte, a metabolite, an organic compound, an organophosphate, adrug, a therapeutic, a gas, a pollutant, or a tag. A biosensor 123 mayinclude an antibody or other binding molecule such as a receptor orligand.

One or more sensors optionally include, in part or whole, a gas sensorsuch as an acoustic wave, chemiresistant, or piezoelectric sensors, oran electronic nose. One or more sensors are optionally small in size,for example a sensor or array that is a chemical sensor (Snow (2005)Science 307:1942-1945), a gas sensor (Hagleitner, et al. (2001) Nature414:293-296.), an electronic nose, and/or a nuclear magnetic resonanceimager (Yusa (2005), Nature 434:1001-1005). Further examples of sensorsare provided in The Biomedical Engineering Handbook, Second Edition,Volume I, J. D. Bronzino, Ed., Copyright 2000, CRC Press LLC, pp.V-1-51-9, and U.S. Pat. No. 6,802,811).

One or more electromagnetic energy sensors 121 may be configured tomeasure the absorption, emission, fluorescence, or phosphorescence ofone or more targets. Such electromagnetic properties may be inherentproperties of all or a portion of one or more targets (e.g.auto-fluorescence), or may be associated with materials added orintroduced to the body, surface, lumen, interior, and/or fluid, such astags or markers for one or more targets. One or more targets mayinclude, but are not limited to, at least a portion of one or more of awound, a lesion, and/or an incision, one or more internal surfaces, oneor more lumen fluids, one or more cells, one or more lumen walls, and/orone or more other interior locations.

In some embodiments, one or more sensors 120 are configured to detect afluorescent response at a single wavelength of electromagnetic energy,at two wavelengths of electromagnetic energy, at multiple wavelengths ofelectromagnetic energy, or over extended-spectrum electromagneticenergy. In some embodiments, one or more sensors 120 are configured todetect excitation energy, ablation energy, and/or targeting energy. Inillustrative embodiments, one or more sensors are configured to detectwavelengths of approximately 100-280 nm, 180-350 nm, 200-340 nm, 250-400nm, 250-450 nm, 280-315 nm, 280-540 nm, 300-460 nm, 300-600 nm, 300-700mm, 310-510 nm, 315-400 nm, 350-390 nm, 350-700 nm, 360-370 nm, 360-600nm, 375-425 nm, 375-440 nm, 400-1000 nm, 407-420 nm, 410-430 nm, 445-470nm, 450-490 nm, 450-560 nm, 455-490 nm, 465-495 nm, 490-690 nm, 505-550nm, 515-555 nm, 580-600 nm, 600-1600 nm, 250 nm, 265 nm, 290 nm, 330 nm,335 nm, 337 nm, 340 nm, 350 nm, 352 nm, 360 nm, 365 nm, 385 nm, 395 nm,400 nm, 405 nm, 410 nm, 420 nm, 430 nm, 435 nm, 436 nm, 440 nm, 444 mm,450 nm, 455 nm, 460 nm, 465 nm, 469 nm, 470 nm, 480 nm, 481 nm, 483 nm,485 nm, 486 nm, 487 nm, 488 nm, 490 nm, 495 nm, 500 mm, 506 mm, 514 nm,516 mm, 520 nm, 530 nm, 538 nm, 545 nm, 546 nm, 550 nm, 560 nm, 570 nm,581 nm, 585 nm, 600 nm, 609 nm, 610 nm, 620 nm, 630 mm, 632 mm, 635 nm,636 nm, 640 nm, 644 nm, 665 nm, 670 nm, 700 nm, 880 nm, 950 nm, 1064 nm,1320 nm, 2070 nm, and/or 2940 nm.

In some embodiments, one or more sensors 120 are configured to detect acumulative fluorescent response over a time interval. In someembodiments, one or more sensors 120 are configured to detect afluorescent response at a specific time interval and/or at a specifictime. In some embodiments, one or more sensors 120 are configured todetect a time-dependent fluorescent response. In illustrativeembodiments, the cumulative fluorescent response is determined overmilliseconds, seconds, and/or minutes following excitation. In someembodiments, the fluorescent response is detected over millisecond,second, and/or minute time intervals following excitation. In someembodiments, the fluorescent response is detected approximatelyfemtoseconds, picoseconds, nanoseconds, milliseconds, seconds, and/orminutes after excitation.

In some embodiments, one or more sensors 120 are configured to becalibrated optionally at least partially based an expected baselinefluorescence (e.g. normal fluorescence) for the fluid, tissue, cells,internal location, lesion, and/or lumen. As used herein, the term“normal fluorescence” may include the intrinsic fluorescence of one ormore fluid, tissue, cells, internal location, lesion, and/or lumen asdetermined by researchers and/or medical or veterinary professionals forsubjects of a certain age, ethnicity, etc. who do not have pathologicalconditions (e.g. control subjects). “Normal fluorescence” may includethe intrinsic fluorescence of fluid, tissue, cells, internal location,lesion, and/or lumen of a subject prior to a pathological conditionand/or of a comparable location not affected by the pathologicalcondition.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 may be configured to detect a condition of interestincluding, but not limited to, a temperature, a pressure, a fluid flow,an optical absorption, optical emission, fluorescence, orphosphorescence, an index of refraction at least one wavelength, anelectrical resistivity, a density or sound speed, a pH, an osmolality,the presence of an embolism, the presence (or absence) of an object(such as a blood clot, a thrombus, an embolus, a plaque, a lipid, akidney stone, a dust particle, a pollen particle, a gas bubble, anaggregate, a cell, a specific type of cell, a cellular component orfragment, a collection of cell, a gamete, a pathogen, or a parasite),and/or the presence (or absence) of a substance such as a biologicalmarker, an antibody, an antigen, a peptide, a polypeptide, a protein, acomplex, a nucleic acid, a cell (and, in some cases, a cell of aparticular type, e.g. by methods used in flow cytometry), a cellularcomponent, an organelle, a gamete, a pathogen, a lipid, a lipoprotein,an alcohol, an acid, an ion, an immunomodulator, a sterol, acarbohydrate, a polysaccharide, a glycoprotein, a metal, an electrolyte,a metabolite, an organic compound, an organophosphate, a drug, atherapeutic, a gas, a pollutant, or a tag, for example.

As used herein, the term “target” may include a condition and/ormaterial of interest. Materials of interest may include, but are notlimited to, materials identifiable by their autofluorescent emissions(individually or as an aggregate signal), or through the use of tagsdetectable through fluorescence. Such materials may include, but are notlimited to, target cells, target tissues, and/or target areas. Suchtargets may include, but are not limited to, a blood clot, a thrombus,an embolus, a plaque, a lipid, a kidney stone, a dust particle, a pollenparticle, an aggregate, a cell, a specific type of cell, a cellularcomponent, an organelle, a collection or aggregation of cells orcomponents thereof, a gamete, a pathogen, or a parasite.

One or more targets may include, but are not limited to, cancer,microbial cells, infected cells, and/or atherosclerotic cells. One ormore cancer cells may include, but are not limited to, neoplastic cells,metastatic cancer cells, precancerous cells, adenomas, and/or cancerstem cells. Cancer types may include, but are not limited to, bladdercancer, breast cancer, colon cancer, rectal cancer, endometrial cancer,kidney (renal) cancer, lung cancer, leukemia, melanoma, non-Hodgkin'sLymphoma, pancreatic cancer, prostate cancer, skin (non-melanoma)cancer, and thyroid cancer. Cancers may include, but are not limited to,bone, brain, breast, digestive, gastrointestinal, endocrine, eye,genitourinary, germ line, gynecological, head and neck,hematologic/blood, leukemia, lymphoma, lung, musculoskeletal,neurologic, respiratory/thoracic, skin, and pregnancy-related. Microbialcells (microorganisms) may include, but are not limited to, bacteria,protists, protozoa, fungi, and/or amoeba. Pathogens may include, but arenot limited to, bacteria, viruses, parasites, protozoa, fungi, and/orproteins. Bacteria may include, but are not limited to, Escherichiacolt, Salmonella, Mycobacterium spp., Bacillus anthracis, Streptococcusspp., Staphylococcus spp., Francisella tularensis, and/or Helicobacterpylori. Viruses may include, but are not limited to, Hepatitis A, B, C,D, and/or E, Influenza virus, Herpes simplex virus, Molluscumcontagiosum, and/or Human Immunodeficiency virus. Protozoa may include,but are not limited to, Cryptosporidium, Toxoplasma spp., Giardialamblia, Trypanosoma spp., Plasmodia spp. and/or Leishmania spp. Fungimay include, but are not limited to, Pneumocystis spp., Tinea, Candidaspp., Histoplasma spp., and/or Cryptococcus spp. Parasites may include,but are not limited to tapeworms and/or roundworms. Proteins mayinclude, but are not limited to, prions.

As used herein, the term “fluid” may refer to liquids, gases, and othercompositions, mixtures, or materials exhibiting fluid behavior. Thefluid within the body lumen may include a liquid, or a gas or gaseousmixtures. As used herein, the term fluid may encompass liquids, gases,or mixtures thereof that also include solid particles in a fluidcarrier. Liquids may include mixtures of two or more different liquids,solutions, slurries, or suspensions. Examples of liquids present withinbody lumens include, but are not limited to, blood, lymph, serum, urine,semen, digestive fluids, tears, saliva, mucous, cerebro-spinal fluid,intestinal contents, bile, epithelial exudate, or esophageal contents.Liquids present within body lumens may include synthetic or introducedliquids, such as blood substitutes, or drug, nutrient, fluorescentmarker, or buffered saline solutions. Fluids may include liquidscontaining dissolved gases or gas bubbles, or gases containing fineliquid droplets or solid particles. Gases or gaseous mixtures foundwithin body lumens may include inhaled and exhaled air, e.g. in thenasal or respiratory tract, or intestinal gases.

Embodiments of one or more apparatus 100 and/or 500 and/or device 200,300, and/or 400 may include control circuitry 130. In some embodiments,the control circuitry is configured to control one or more of one ormore energy sources 110, one or more sensors 120, and/or one or morepower sources 140. In some embodiments, the control circuitry 130 may bedirectly coupled, indirectly coupled, and/or wirelessly coupled to oneor more energy sources 110, one or more sensors 120, and/or one or morepower sources 140. Control circuitry 130 may be electrical circuitryand/or other types of logic/circuitry including, for example, fluidcircuitry, chemo-mechanical circuitry, and other types oflogic/circuitry that provide equivalent functionality. The controlcircuitry 130 may include at least one of hardware, software, andfirmware; in some embodiments the control circuitry may include amicroprocessor. The control circuitry 130 may be located in or on thestructural element of a device and/or at a location separate from thestructural element. Various operation flows (e.g. 600, 700, and/or 800)operable on control circuitry 130 are described herein and/or known inthe art.

In some embodiments, the control circuitry 130 is responsive to identifya target, target area, and/or target cells, molecules, and/or tissues.In some embodiments, the control circuitry 130 identifies a target,target area, and/or target cells, molecules, and/or tissues bydetermining one or more of the direction, the distance, the tissuedepth, the time, and/or the coordinates from which a fluorescentresponse originated, optionally in relation to the excitation energy 116and/or the targeting energy 118. In some embodiments, the controlcircuitry 130 identifies a target, target area, and/or target cells,molecules, and/or tissues by analysis of one or more characteristics ofa fluorescent response (e.g. presence and/or absence of a fluorescentresponse and/or density of a fluorescent response—grouping of cells thatif non-grouped would not be considered a target), optionally includingbut not limited to, the electromagnetic spectrum, or parts thereof, of afluorescent response. In some embodiments, the control circuitry 130identifies a target, target area, and/or target cells, molecules, and/ortissues in real time.

In some embodiments, the control circuitry 130 is responsive to selectone or more characteristics of ablation energy 117 for at leastpartially ablating a target, target area, and/or target cells,molecules, and/or tissues. In some embodiments, the control circuitry130 selects one or more characteristics of ablation energy 117 for atleast partially ablating a target, target area, and/or target cells,molecules, and/or tissues responsive to one or more characteristics ofthe fluorescent response and/or the electromagnetic energy selected toelicit the fluorescent response. In some embodiments, the controlcircuitry 130 increases the ablation energy 117 responsive to anincrease in the fluorescent response, and/or decreases the ablationenergy 117 responsive to a decrease in the fluorescent response. In someembodiments, the control circuitry 130 selects one or morecharacteristics of the ablation energy 117 at least partially responsiveto detection of one or more wavelengths of the fluorescent response.

In some embodiments, the control circuitry 130 is responsive to updatetargeting information on the basis of movement of part or all of anapparatus 100, and/or 500 and/or a device 100, 200, and/or 300 and/or atarget and/or target area. In illustrative embodiments, such targetupdating may be useful when the ablating energy 117 may be delivered ata time substantially later than the time at which autofluorescenceradiation is detected, or when the target is moving in relation to theablation energy source 117. In this case, the detected location must beupdated to take into account possible motion of the target area and/orthe device.

Motion of the autofluorescence location can be updated by registeringthe detected autofluorescence location relative to other, updatable,location information. In one example, the detected autofluorescencelocation is registered relative to fiducials on or within theindividual. Then, the location of the fiducials is updated, and the siteof the autofluorescence location at such time can be predicted basedupon its known registration relative to the fiducial locations. Inanother example, the detected autofluorescence location is registeredrelative to features within an image of a related portion of theindividual. Then, the image is updated and the location of theautofluorescence location at such time can be predicted based upon itsknown registration relative to the image features.

Motion, which may include location and/or orientation, of the device canbe updated by a variety of methods, including inertial navigation,measurements based on beacons or fiducials, measurements based onorientation sensors, or combinations of such techniques. Inertialnavigation can be performed with the support of accelerometers on thedevice, and may also incorporate use of gyroscopic sensors on thedevice. Beacons and/or fiducials can be used to measure the device'smotion; the beacons or fiducials may be on the device and their locationor direction measured by remote sensors. Alternatively, measurements ofremote beacons or fiducials may be made by sensors on the device.Combined systems may be used, with mixtures of remote and on-boardsensors, measuring the location or direction of remote or on-boardbeacons or fiducials. Orientation sensors, such as tilt sensors may beused to provide information of one or more aspects of the device'sorientation. Motion information obtained from different sources ormethods can be combined together to give improved motion estimates,using techniques such as nonlinear filtering, least-squares filtering,Kalman filtering, etc.

The updated autofluorescence location may then be combined, via acoordinate translation and rotation, with the updated position andlocation of the device. This results in updated coordinates ordirections of the autofluorescence location with respect to the device,and can be used to direct the delivery of ablation energy.

In some embodiments, control circuitry receives information from one ormore sensors and/or one or more external sources. Information mayinclude, but is not limited to, a location of an untethered device,allowable dose limits (e.g. of energy for excitation and/or ablationand/or targeting), release authority (e.g. for release of energy forexcitation, ablation, and/or targeting, and/or release from a tetheredlocation, or from an affixed and/or stationary location), controlparameters (e.g. for energy release, for motion, for power, for sensors,etc.), operating instructions, and/or status queries.

In some embodiments, control circuitry is feedback controlled,optionally from information from one or more sensors, and/or one or moreexternal sources. In some embodiments, control circuitry is monitored byone or more external sources, provides outputs to one or more sources,and/or sends outputs to one or more sources. In some embodiments controlcircuitry is remote-controlled, wirelessly controlled, programmed,and/or automatic.

Embodiments of one or more apparatus 100 and/or 500 and/or devices 200,300 and/or 400 optionally include a power source 140. One or more powersources may be configured to provide power to one or more of one or moremotive sources, one or more control circuitry, one or more sensor,and/or one or more energy source.

Power sources 140 may include, but are not limited to, one or morebatteries 141, fuel cells 142, energy scavenging 143, electrical 144,and/or receivers 145 located on and/or in the one or more apparatusand/or devices or separately from the one or more apparatus and/ordevices. The one or more batteries may include a microbattery such asthose available from Quallion LLC (http://www.quallion.com), may bedesigned as a film (U.S. Pat. Nos. 5,338,625 and 5,705,293), or may be anuclear battery. The one or more fuel cells may be enzymatic, microbial,or photosynthetic fuel cells or other biofuel cells (US2003/0152823A1;WO03106966A2 Miniature Biofuel cell; Chen T et al. J. Am. Chem. Soc.2001, 123, 8630-8631, A Miniature Biofuel Cell), and may be of any size,including the micro- or nano-scale.

The one or more energy-scavenging devices may include apressure-rectifying mechanism that utilizes pulsatile changes in bloodpressure, for example, or an acceleration-rectifying mechanism as usedin self-winding watches, or other types of flow rectifying mechanismscapable of deriving energy from other flow parameters. The one or moreelectrical power sources may be located separately from the structuralelement of the device and connected to the structural element by a wire,or an optical power source located separately from the structuralelement and connected to the structural element by a fiber-optic line orcable. The one or more power receivers may be capable of receiving powerfrom an external source, acoustic energy from an external source, and/ora power receiver capable of receiving electromagnetic energy (e.g.,infrared energy) from an external source.

In illustrative embodiments, one or more power sources 140 areoptionally part of and/or are configured to propel, move, and/or providepower to one or more motive sources 150. One or more of the propellingmechanisms may include mechanical or micromechanical structures drivenby at least one motor, micromotor, or molecular motor, or by expansionor change in configuration of a shape change polymer or metal. Amolecular motor may be a biomolecular motor that runs on a biologicalchemical such as ATP, kinesin, RNA polymerase, myosin dynein,adenosinetriphosphate synthetase, rotaxanes, or a viral protein. Inillustrative embodiments, one or more power sources 140 are configuredto power one or more rotary motors, propellers, thrusters, and/orprovide for jet propulsion, among others.

In some embodiments, the power source 140 optionally includes a powertransmitter capable of transmitting power from one or more device to asecondary location. The power transmitter may be capable of transmittingat least one of acoustic power, electrical power, or optical power. Thesecondary location may be, for example, another device within the body,either in a body lumen or elsewhere that includes a power receiver andstructures for using, storing and/or re-transmitting the received power.

Embodiments of one or more devices 200, 300 and/or 400 may include oneor more motive sources 150. The one or more motive sources 150 areconfigured for the type and nature of the lumen and/or internal locationto be traveled. A lumen and/or internal location having a relativelyuniform cross-section (height and/or width) over the length to betraveled may be traversed by most propelling mechanisms including, butnot limited to, mechanisms that engage the lumen wall on more than oneand/or several sides, that engage the lumen wall on one side only, thatare able to change shape/size (see, e.g., U.S. Patent Application2005/0177223), and/or that employ more than one means of propulsion. Alumen and/or internal location that varies significantly incross-section over the length to be traveled may be traversed using somepropelling mechanisms including, but not limited to, those that walk orroll along one side of a lumen, those that are able to changeshape/size, and/or those that employ more than one mode of propulsion.

In illustrative embodiments, one or more motive sources 150 mayencompass part or all of the structural elements of one or more devices200, 300, and/or 400. For example, one or more structural elements ofone or more devices may be substantially cylindrical, and hollow andtubular in configuration, with a single central opening, optionallyallowing the exterior of the cylindrical structural element to contactand engage the wall of a lumen, and the interior of the structuralelement (within the single central opening) to optionally form afluid-contacting portion of the structural element. Optionally, one ormore structural elements of one or more devices may be approximatelyhemi-spherical or hemi-elliptoid, optionally allowing a portion of itscross-section to contact and/or engage the wall of a lumen withoutobstructing the movement of fluid within the body lumen. Optionally, oneor more structural elements of one or more devices may be pill- orcapsule-shaped, and adapted to move through a central portion of a bodylumen. Lumen wall engaging portions may include, but are not limited to,rotating wheels, projections (e.g. arms), springs, hooks (e.g. claws),and/or tissue adhesives that are configured to engage wall portions andoptionally to provide mobility to one or more devices.

A variety of motive sources 150 applicable for one or more devices areknown in the art and/or described herein. See, for example, U.S. Pat.Nos. 5,337,732; 5,386,741; 5,662,587; and 6,709,388; and Kassim, et al.“Locomotion Techniques for Robotic Colonoscopy”; IEEE Engineering in Med& Biol. Mag. (2006) pp. 49-56; Christensen “Musclebot: Microrobot with aHeart” (2004) Technolegy.com, pp. 1-2 located athttp://www.technovelgy.com/ct/Science-Fiction-News.asp?NewsNum=46;Ananthaswamy “First robot moved by muscle power” (2004), pp. 1-3; NewScientist; located at http://www.newscientist.com/article.ns?id=dn4714;and Freitas “8.2.1.2 Arteriovenous Microcirculation”; “9.4.3.5 LeggedAmbulation”; “9.4.3.6 Tank-Tread Rolling”; “9.4.3.7 AmoeboidLocomotion”; “9.4.3.8 Inchworm Locomotion”; “Nanomedicine Volume I:Basic Capabilities” (1999) pp. 211-214, pp. 316-318; Landes Bioscience;Georgetown, Tex., USA.

One or more motive source 150 may include, but is not limited to, one ormore propelling mechanisms such as one or more cilium-like structures(see, e.g., U.S. Patent Application 2004/0008853; Mathieu, et al. “MRISystems as a Mean of Propulsion for a Microdevice in Blood Vessels”(2003) pp. 3419-3422, IEEE; Lu, et al. “Preliminary Investigation ofBio-carriers Using Magnetotactic Bacteria”; Proceedings of the 28th IEEEEMBS Annual International Conference (2006); pp. 3415-3418 IEEE, andMartel “Towards MRI-Controlled Ferromagnetic and MC-1 MagnetotacticBacterial Carriers for Targeted Therapies in Arteriolocapillar NetworksStimulated by Tumoral Angiogenesis” Proceedings of the 28th IEEE EMBSAnnual International Conference (2006) pp. 3399-3402 IEEE.

One or more motive source 150 may include propelling mechanisms such as,but not limited to, rollers or wheel-like structures (see, e.g., U.S.Pat. No. 7,042,184 and U.S. Patent Application 2006/0119304; screw-likestructures (see, e.g., Ikeuchi, et al. “Locomotion of Medical MicroRobot with Spiral Ribs Using Mucus” Seventh International Symposium onMicro Machine and Human Science (1996) pp. 217-222 IEEE); and/orappendages capable of walking motion (see, e.g., U.S. Pat. No.5,574,347; Shristensen “Musclebot: Microrobot with a Heart”Technovelgy.com; pp. 1-2; (2004); located athttp://www.technovelgy.com/ct/Science-Fiction-News.asp?NewsNum=46; andMartel “Fundamentals of high-speed piezo-actuated three-legged motionfor miniature robots designed for nanometer-scale operations” pp. 1-8),and others. Appendage-like structures may intermittently engage thelumen wall and push the structural element with respect to the lumenwall with a walking-type motion, or may push against fluid within thelumen in a paddling or swimming motion. In some embodiments, thepropelling mechanism may drive rotational movement of alumen-wall-engaging structure with respect to the structural element,e.g., as in turning of a wheel or a screw element to propel thestructural element through a lumen.

One or more motive source 150 may include propelling mechanisms such as,but not limited to, an inchworm-type propulsion mechanism with suctionmechanisms for engaging a surface (see, e.g., Patrick, et al. “ImprovedTraction for a Mobile Robot Traveling on the Heart”, Proceedings of the28^(th) IEEE EMBS Annual International Conference (2006) pp. 339-342IEEE; Dario, et al. “A Micro Robotic System for Colonoscopy” Proceedingsof the 1997 IEEE International Conference on Robotics and Automation(1997) pp. 1567-1572 IEEE; and Dongxiang, et al. “An earthworm basedminiature robot for intestinal inspection” Proceedings of SPIE (2001)4601:396-400 SPIE).

One or more motive source 150 may include propelling mechanisms such as,but not limited to, multiple lumen wall engaging structures, operatingin sequence to alternately engage and disengage the lumen wall, toproduce “peristaltic” motion (see, e.g., U.S. Pat. No. 6,764,441; U.S.Patent Application 2006/0004395; Mangain, et al. “Development of aPeristaltic Endoscope” IEEE International Conference on Robotics &Automation 2002; pp. 1-6;http://biorobots.cwru.edu/publications/ICRA02_Mangan_Endoscope.pdf; andMeier, et al. “Development of a compliant device for minimally invasivesurgery” Proceedings of the 28^(th) IEEE EMBS Annual InternationalConference (2006) pp. 331-334 IEEE).

One or more motive source 150 may include propelling mechanisms such as,but not limited to, one or more paddles, propellers, or the like, whichpush against fluid contained within the lumen rather than engaging thewall of the body lumen (see, e.g., U.S. Pat. No. 6,240,312; and Behkam,et al. Proceedings of the 28^(th) IEEE EMBS Annual InternationalConference (2006) pp. 2421-2424 IEEE.

One or more motive source 150 may include mechanisms configured to allowaffixation to a lumen wall or other interior location, either permanentor temporary. In illustrative embodiments, configurations for affixingmay include, but are not limited to, one or more anchors configured toattach at least temporarily to a wall of the lumen, one or more hooksand/or claws, one or more adhesive materials and/or glues, one or morebrakes to oppose the action of the propelling mechanism, one or moreexpanding elements, one or more suction-generating elements, and/or or ashutoff for the propelling mechanism and/or for one or more power source140.

In some embodiments, one or more configurations for affixing one or moredevices may be activated responsive to control circuitry. In someembodiments, one or more configurations for affixing one or more devicesmay be fixed or movable. Movable structures may include, but are notlimited to, mechanical elements and/or materials that change shape orrigidity in response to temperature, electric field, magnetic field, orvarious other control signals. Affixation may be permanent, for extendedperiods, and/or temporary. As used herein, the term “extended periods”may include weeks to months to years and subsets thereof. As usedherein, the term “temporary” may include seconds, to minutes, to hours,to days and subsets thereof.

One or more motive source 150 may include mechanisms configured to allowone or more device to become stationary relative to a flow of fluidthrough a lumen and/or an internal location. In illustrativeembodiments, configurations for becoming stationary include, but are notlimited to, becoming affixed to a lumen or other internal location (e.g.by one or more mechanism described above), and/or reversing thepropelling mechanism. Illustrative embodiments of configurations forreversing a propelling mechanism include, but are not limited to,reverse orientation of one or more motive source 150 (e.g. oriented toprovide motive force in a reverse direction, such as against the flow offluid, for example), one or more motive source 150 configured to allowbi-directional orientation (e.g. provide motive force in two directions,optionally 180 degrees apart (in opposition)), and/or one or more motivesource configured to allow motive force to be applied in variableorientations.

In one aspect, the disclosure is drawn to one or more methods forablating one or more targets optionally at least partially based on afluorescent response, optionally using one or more apparatus 100 and/or500 and/or device 200, 300 and/or 400 described herein. Although one ormore methods may be presented separately herein, it is intended andenvisioned that one or more methods and/or embodiments of one or moremethods may be combined and/or substituted to encompass the fulldisclosure. In some embodiments, one or more methods may include one ormore operations, and be implemented using one or more computing devicesand/or systems.

In some embodiments, one or more methods of treatment include providingto a lesion electromagnetic energy selected to induce a fluorescentresponse from a target area; detecting the fluorescent response;identifying the target area at least partially based on an analysis ofthe detected fluorescent response; and providing energy to at leastpartially ablate the identified target area in real time. In someembodiments, one or more methods for ablating one or more target cellsinclude providing to a lesion electromagnetic energy selected to inducea fluorescent response from a target area; detecting the fluorescentresponse; identifying the target area at least partially based on ananalysis of the detected fluorescent response; and providing energy toat least partially ablate the identified target area in real time.

In some embodiments, one or more methods for detecting and ablating atarget area include providing an untethered device to a lumen of asubject; providing from the untethered device electromagnetic energyselected to induce an auto-fluorescent response in one or more targetcells in proximity to the lumen; detecting the auto-fluorescent responseusing a sensor in the untethered device; identifying the target area atleast partially based on an analysis of the detected auto-fluorescentresponse; and providing from the untethered device energy configured toat least partially ablate the identified target area. In someembodiments, one or more methods of treatment include providing anuntethered device to a lumen of a subject; providing from the untethereddevice electromagnetic energy selected to induce an auto-fluorescentresponse in one or more target cells in the lumen; detecting theauto-fluorescent response using a sensor in the untethered device;identifying the target area at least partially based on an analysis ofthe detected auto-fluorescent response; and providing from theuntethered device electromagnetic energy configured to at leastpartially ablate the identified target area.

In some embodiments, one or more methods for treating or ameliorating H.pylori infection include providing to a digestive tract of a subject anuntethered ingestible mass, the untethered ingestible mass configuredfor non-uniform movement; and emitting electromagnetic energy from theuntethered ingestible mass in a manner selected to induce photodynamiccell death in H. pylori. In some embodiments, one or more methods forablating H. pylori include providing to a digestive tract of a subjectan untethered ingestible mass, the untethered ingestible mass configuredfor non-uniform movement; and emitting electromagnetic energy from theuntethered ingestible mass in a manner selected to induce photodynamiccell death in H. pylori.

In some embodiments, one or more methods for detecting and ablating atarget area in a digestive tract include providing to a subject anoptionally rotating untethered ingestible mass and/or optionallyconfigured for non-uniform movement; providing from the untetheredingestible mass electromagnetic energy selected to induce anauto-fluorescent response in one or more target cells in the digestivetract; detecting the auto-fluorescent response using a sensor in theuntethered device; identifying the target area at least partially basedon an analysis of the detected auto-fluorescent response; and providingfrom the untethered device electromagnetic energy configured to at leastpartially ablate the identified target area. In some embodiments, one ormore methods for treating a disease or disorder in a digestive tractinclude providing to a subject a rotating untethered ingestible mass;providing from the untethered ingestible mass electromagnetic energyselected to induce an auto-fluorescent response in one or more targetcells in the digestive tract; detecting the auto-fluorescent responseusing a sensor in the untethered device; identifying the target area atleast partially based on an analysis of the detected auto-fluorescentresponse; and providing from the untethered device electromagneticenergy configured to at least partially ablate the identified targetarea. In some embodiments, one or more methods of treatment includeproviding to a subject a rotating untethered ingestible mass; providingfrom the untethered ingestible mass electromagnetic energy selected toinduce an auto-fluorescent response in one or more target cells in thedigestive tract; detecting the auto-fluorescent response using a sensorin the untethered device; identifying the target area at least partiallybased on an analysis of the detected auto-fluorescent response; andproviding from the untethered device electromagnetic energy configuredto at least partially ablate the identified target area.

In some embodiments, one or more methods for detecting and ablating oneor more target cells include providing to an internal location atethered device; providing from the tethered device electromagneticenergy selected to induce an auto-fluorescent response from the one ormore target cells; detecting the auto-fluorescent response; identifyinga target area at least partially based on an analysis of the detectedauto-fluorescent response; and providing energy to at least partiallyablate the identified target area in real time. In some embodiments, oneor more methods of treatment include providing to an internal location atethered device; providing from the tethered device electromagneticenergy selected to induce an auto-fluorescent response from one or moretarget cells; detecting the auto-fluorescent response; identifying atarget area at least partially based on an analysis of the detectedauto-fluorescent response; and providing energy to at least partiallyablate the identified target area in real time.

Embodiments of one or more methods include affixing one or more devices200, 300, and/or 400 to a location in a lumen and/or an interiorlocation. As used herein, the term “affixing” may include, but is notlimited to one or more processes by which the one or more devices may beheld stationary in the lumen or internal location. The affixation may betemporary and/or permanent as described herein. Mechanisms by which oneor more device may become affixed are known in the art and/or describedherein.

Embodiments of one or more methods include moving one or more devices200, 300, and/or 400 from one location to another within a lumen and/orinternal location. As used herein, the term “moving” may include, but isnot limited to, one or more processes by which a device may traverse alumen and or internal location in one or more directions. Movement maybe with the flow of an optional moving fluid (and/or gravity), againstthe flow of an optional moving fluid (and/or gravity), and or at anangle oblique to a moving flow of fluid (and/or gravity). Movement maybe irrespective of the presence and/or absence of fluid and/or movingfluid. Movement may be temporary, intermittent, and/or continuous.Movement may be random and/or non-uniform. Movement may be controlled bycontrol circuitry, either internal or external to the device. Movementmay be associated with identification and/or ablation of a target.Mechanisms for moving one or more device are known in the art and/or aredescribed herein.

In illustrative embodiments, moving an untethered device includes movingan untethered device by providing a motive force to the untethereddevice. As used herein, the term “motive force” may include, but is notlimited to, a mechanism that allows the untethered device to move withina lumen and/or internal location, such as for example, those describedfor a motive source and a power source herein. In some embodiments, amotive force is responsive to control circuitry, is remote-controlled,is programmable, and/or is feedback-controlled. In some embodiments, amotive force is powered by a battery, a capacitor, receives power fromone or more external sources, and/or from one or more physiologicalsources. In some embodiments, a motive force is responsible for therandom and or non-uniform movement of a device.

Embodiments of one or more methods include providing electromagneticenergy, optionally optical energy, to a target, target area, targetcell, target tissue, lesion, incision, wound, internal location, and/orlumen, optionally selected to induce a fluorescent response. Providingelectromagnetic energy optionally includes using a laser, optionallyhandheld, or other device to provide optical energy to a target.

Parameters associated with the selection of electromagnetic energy toinduce a fluorescent response include, but are not limited to, thetarget, the environment associated with the target, the characteristicsof the electromagnetic energy source, and/or the characteristics of thesensor.

The parameters associated with the target include, but are not limitedto, the distance of the target from the electromagnetic source, thedepth of the target beneath a surface (e.g. a lumen wall, an internalsurface, a lesion surface), the inherent fluorescence of the target, themarkers/tags used to identify the target, the size of the target, and/orthe movement of the target (e.g. stationary, steady movement, variablemovement, predictable movement, etc.).

The parameters associated with the environment include, but are notlimited to, location (e.g. external, internal, lumen, wound, incision,etc.), milieu (e.g. fluid-filled, air-filled, blood, digestive contents,etc.), movement (e.g. stationary, steady movement, intermittentmovement, predictable movement, etc.), physiologic parameters (e.g. pH,temperature, etc.), and/or non-target fluorescence (e.g. backgroundfluorescence, non-specific fluorescence, intrinsic non-target fluoresce,etc.).

The parameters associated with the characteristics of theelectromagnetic energy source include, but are not limited to, thewavelengths available for selection (e.g. single, two-photon, multiple,extended-spectrum, etc.), the strength of the emitted electromagneticenergy (e.g. limitations on distance and/or depth, etc.), the type ofoutput (e.g. pulsed, two-photon, etc.), directionality (e.g. limited,variable, varied, etc.), and/or spatial parameters (e.g. limited,focused, collimated, etc.).

The parameters associated with the characteristics of the sensorinclude, but are not limited to, the detection limits associated withwavelength (e.g. single, two-photon, multiple, extended-spectrum, etc.),signal strength (e.g. sensitivity of detection, level above background,etc.), and/or time (e.g. detects cumulative readings over time, detectsreadings at certain time intervals, or at a certain time postexcitation, etc.).

Embodiments of one or more methods include selecting the electromagneticenergy, optionally optical energy, to induce the fluorescent response.Methods for selecting include, but are not limited, manually, remotely,automatically, programmably, wirelessly, and/or using control circuitry.Manually selecting includes, but is not limited to, manually operatingone or mechanism (e.g. a switch, dial, button, etc.) on one or moreapparatus 100 and/or 500, and/or device 200, 300, and/or 400, thatcontrols the emitted wavelength from one or more electromagnetic energysource. Remotely selecting includes, but is not limited to, optionallywirelessly interacting with circuitry on one or more apparatus 100and/or 500, and/or device 200, 300, and/or 400 that controls thewavelength emitted from one or more electromagnetic energy source.Programmably selecting includes, but is not limited to, optionally usingcontrol circuitry, optionally part of one or more apparatus 100 and/or500, and/or device 200, 300, and/or 400 (e.g. internal and/or external),programmed, optionally manually, remotely, and/or wirelessly, to selectthe wavelength emitted from one or more electromagnetic energy source.Methods for programming control circuitry are well-known to one of skillin the art, and some applicable control circuitry is described herein.

Embodiments of one or more methods include monitoring theelectromagnetic energy selected to induce a fluorescent response,optionally an auto-fluorescent response, optionally a target fluorescentresponse, monitoring the energy selected to ablate the target,optionally electromagnetic energy, optionally particle beam energy,and/or monitoring the targeting electromagnetic energy, optionallyvisual light. Methods of monitoring electromagnetic energy and/orparticle beam energy are known in the art and/or described herein.Methods include, but are not limited to, using sensors able to detectone or more characteristics of the energy.

Embodiments of one or more methods include detecting a fluorescentresponse. Methods of detecting a fluorescent response include, but arenot limited to, detecting a fluorescent response using one or moresensors, detectors, and/or monitors. Sensors, detectors, and/or monitorsappropriate for detection and/or monitoring of the fluorescent responseare known in the art and/or described herein. As used herein, the term“detecting” may include any process by which one or more characteristicsof a fluorescent response may be measured and/or quantified.

Embodiments of one or more methods include identifying a target forablation (e.g. target area, target cells, and/or target tissues). Asused herein, the term “identifying a target” may include, but is notlimited to, processes including selecting a target and/or determining atarget. One or more methods for identifying a target for ablationoptionally include analyzing a fluorescent response and/or otherinformation, optionally using control circuitry, optionally in realtime.

Analyzing a fluorescent response to at least partially identify a targetfor ablation may include, but is not limited to, evaluating afluorescent response at least partially in reference to baselinefluorescence, background fluorescence, expected fluorescence, normalfluorescence, reference fluorescence, non-specific fluorescence, and/orintrinsic non-target fluorescence, etc. Analyzing a fluorescent responsemay include, but is not limited to, subtractively determining a targetfluorescent response (e.g. subtracting the non-target fluorescence fromthe total fluorescence to determine the target fluorescence). Analyzinga fluorescent response may include, but is not limited to, evaluating afluorescent response at least partially based on detection at one ormore wavelengths (e.g. single, multiple, extended-spectrum, etc.), basedon time (e.g. one or more times, time intervals, and/or over time,etc.), based on direction (e.g. of origination of the emission, etc.),based on strength, and/or based on distance (e.g. of origination ofemission from a sensor). In illustrative embodiments, analyzing afluorescent response may include, but is not limited to, identifying“clumps” and/or “groups” of autofluorescent cells that in anothercontext might be considered “normal”, but that are not normally groupedand so may be a target for ablation.

In illustrative embodiments, an analyzed target fluorescent response isused to determine the direction from which the response originated inorder to provide ablation energy to the location and/or general area. Inillustrative embodiments, an analyzed target fluorescent response isused to determine the coordinates from which the response originated inorder to provide ablation energy to the location and/or general area.

As used herein, the term “location” may include, but is not limited to,one or more of a direction, an area, a depth, a site, or a size, etc. Alocation may be defined by spatial coordinates and/or temporalcoordinates. A location may be defined as precisely as the cellularlevel, for example, or as broadly as a general area, or a generaldirection. Methods of determining a location based on the detection of afluorescent response are known in the art and/or described herein. Inillustrative embodiments, a target location may be the cancerous and/orpre-cancerous cells remaining in a surgical margin. In illustrativeembodiments, a target location may be the microbial cell contaminationremaining in a wound following a sterile wash. In illustrativeembodiments, a target location may be the lumen of a blood vesselfollowing detection of a target fluorescent response. In illustrativeembodiments, a target location may be the lumen of the digestive tractin a area with an acidic pH.

Analyzing other information to at least partially identify a target forablation may include, but is not limited to, analyzing informationoptionally provided by one or more sensors (e.g. intrinsic and/orextrinsic to one or more device and/or apparatus) and/or provided by oneor more external sources (e.g. remotely and/or wirelessly, etc.).Analyzing information optionally provided by one or more sensors mayinclude analyzing information including, but not limited to,environmental information such as, but not limited to, pH, temperature,pressure, chemistry, physiological measurements, dietary measurements,biological measurements, etc. In illustrative embodiments, identifying atarget fluorescent response is a least partially based on identifyingthe pH of the environment, optionally detecting an acidic pH. Analyzinginformation optionally provided by one or more external sources mayinclude analyzing information including, but not limited to,environmental information and/or medical and/or veterinary professionalinformation.

Analyzing a fluorescent response to at least partially identify a targetfor ablation may include, but is not limited to, evaluating afluorescent response in real time. As used herein, the term “in realtime” may include, but is not limited to, immediate, rapid, notrequiring operator intervention, automatic, and/or programmed. In realtime may include, but is not limited to, measurements in femtoseconds,picoseconds, nanoseconds, milliseconds, as well as longer, andoptionally shorter, time intervals. In illustrative embodiments,analysis in real time is sufficiently rapid such that the target and thedevice have not moved and/or changed positions/locations significantlywith respect to each other. In illustrative embodiments, a fluorescentresponse is detected and analyzed, and a target is identified withoutoperator intervention and the target ablation information is provided toan energy source.

Embodiments of one or more methods include providing energy to at leastpartially ablate a target. One or more methods include providing energyto at least partially ablate a target in real time. As used herein theterm “ablation or ablate” may include, but is not limited to, processesincluding destroying, modifying, removing, and/or eliminating, in partor in whole, a target and/or a material of interest. As used herein,ablation may include the process of removing material, optionally from asurface, by irradiating it, optionally with a laser beam. At low laserflux, the material is heated by the absorbed laser energy and evaporatesor sublimes. At high laser flux, the material is typically converted toa plasma. Ablation may include the process of removing material with apulsed laser, or a continuous wave laser.

Energy for ablation may include, but is not limited to, electromagneticenergy, X-ray energy, and particle beam energy. Electromagnetic energysuch as light may cause, for example, a photoreaction, molecular bondbreakage, heating, or other appropriate effect. Electromagnetic energysources may include, but are not limited to, light sources such as lightemitting diodes and laser diodes, or sources of other frequencies ofelectromagnetic energy, radio waves, microwaves, ultraviolet rays,infra-red rays, optical rays, terahertz beams, and the like.

As used herein, the term “at least partially ablate” may includepartially and/or completely ablating a target. As used herein, the term“completely ablate” may include ablation of a target up to theapplicable limits of detection (e.g. no longer detectable by the sensorsused to detect the fluorescent response, no longer detectable overbackground, and/or no longer statistically significant). As used hereinthe term “partially ablate” may include ablation less than completeablation, but where at least some detectable ablation occurs. At leastsome detection ablation includes, but is not limited to, ablationdetectable by the sensors used to detect the fluorescent response,statistically significant ablation, detection by external sensors,and/or detection by inference from other measurements and/or sensorreadouts.

Embodiments of one or more methods include providing targetingelectromagnetic energy to a lesion, a lumen, an internal location, etc.methods for providing targeting electromagnetic energy are known in theart, and/or described herein. Targeting electromagnetic energy isoptionally optical energy, optionally visible to the human eye.Targeting electromagnetic energy is optionally alignable withelectromagnetic energy emitted to induce a fluorescent response and/orwith energy emitted to at least partially ablate a target. Inillustrative embodiments, targeting electromagnetic energy is alignedwith the output from one or more energy sources as a visual aid to amedical and/or veterinary professional during treatment of a subject.

EXAMPLES

The following Examples are provided to illustrate, not to limit, aspectsof the present invention. Materials and reagents described in theExamples are commercially available unless otherwise specified.

Example 1 Detection and Ablation of Pathogens Prior to Closing aSurgical Incision

A surgical incision is screened with a device that detects and ablatespathogens within the open lesion prior to closing to preventpostoperative infection. The device emits electromagnetic energy atwavelengths sufficient to induce autofluorescence of pathogens withinthe incision. The device detects the autofluorescence associated withthe pathogens, and in real time automatically delivers energy sufficientto at least partially inactivate or ablate the pathogens. Optionally,the device detects the autofluorescence, collects and processes thedata, and at the discretion of the surgeon or other medical practitioner(or veterinarian), a trigger mechanism, for example, is used to deliverenergy sufficient to at least partially inactivate or ablate thepathogens at the coordinates associated with the autofluorescence. Thedevice may be handheld, for example, and either self-contained orconnected wirelessly or by wire to optionally a power supply, energysources, control circuitry, and/or monitor. Alternatively, the devicemay be a fixed component of the surgical theater.

A pathogen or pathogens may be detected at the site of incision based onautofluorescence induced, for example, by electromagnetic energy.Naturally occurring autofluorescence in bacteria, for example, isderived from biomolecules containing fluorophores, such as porphyrins,amino acids tryptophan, tyrosine, and phenylalanine, and the coenzymesNADP, NADPH, and flavins (Koenig, et al. (1994) J. Fluoresc. 4:17-40;Kim, et al. (2004) IEEE/EMB Magazine January/February 122-129). Theexcitation maxima of these biomolecules lie in the range of 250-450 nm(spanning the ultraviolet/visible (UV/VIS) spectral range), whereastheir emission maxima lie in the range of 280-540 (spanning the UV/VISspectral range; Ammor (2007) J. Fluoresc. published on-line ahead ofpublication).

For example, two clinically important bacteria, Enterococcus faecalis,and Staphylococcus aureus, may be differentiated based on theirrespective autofluorescence in response to excitation spectra of 330-510nm and emission spectra of 410-430 nm (Ammor (2007) J. Fluoresc.published on-line ahead of publication). Similarly, Streptococcuspneumoniae, Moraxella catarrhalis, and Haemophilus influenzae may bedetected using fluorescence spectroscopy at excitation wavelengths of250 and 550 nm and emission wavelengths of 265 and 700 nm (Ammor (2007)J. Fluoresc. published on-line ahead of publication). Bacteriaassociated with community acquired pneumonia, Legionella anisa andLegionella dumoffii, autofluoresce blue-white when exposed to long-wave(365-nm) UV light (Thacker, et al. (1990) J. Clin. Microbiol.28:122-123). Bacillus spores will autofluoresce when excited by UVirradiation at a wavelength of 352 nm (Laflamme, et al. (2006) J.Fluoresc. 16:733-737). Clostridium sporogenes, Pseuodomonas aeruginose,Pseudomonas fluorescens, Kocuria rhizophila, Bacteroides vulgatis,Serratia marcescens, and Burkholderia cepacia emit yellow-greenfluorescent signal when illuminated with blue light (Sage, et al. (2006)American Biotechnology Laboratory 24:20-23).

Autofluorescence of endogenous porphyrins may also be used to detectbacteria. A number of bacteria produce protoporphyrins, includingPropinibacterium acnes, Bacillus thuringiensis, Staphylococcus aureus,and some strains of Clostridium, Bifidobacterium, and Actinomyces(Koenig, et al. (1994) J. Fluoresc. 4:17-40). Bacteria may also bedetected using fluorescence lifetimes measured at 430, 487, and 514 nmafter selective excitation at 340, 405, and 430 nm (Bouchard, et al.(2006) J. Biomed. Opt. 11:014011, 1-7).

Autofluorescence may also be used to detect members of the fungi family.For example, Candida albicans irradiated with electromagnetic energy atwavelengths of 465-495 nm autofluoresces at an emission wavelength of515-555 nm (Mateus, et al. (2004) Antimicrob. Agents and Chemother.(2004) 48:3358-3336; Graham (1983) Am. J. Clin. Pathol. 79:231-234).Similarly, Aspergillus niger and Aspergillus versicolor may be detectedusing autofluorescence in response to excitation at 450-490 nm andemission at 560 nm (Sage, et al. (2006) American BiotechnologyLaboratory 24:20-23; Graham (1983) Am. J. Clin. Pathol. 79:231-234).

A pathogen or pathogens at the site of incision may be inactivated orkilled by energy emitted from a device in response to detection of thepathogen by autofluorescence using the same device. Many pathogens areinactivated or killed by UV germicidal irradiation (Anderson, et al.(2000) IEEE Transactions on Plasma Science 28:83-88; Hancock, et al.(2004) IEEE Transactions on Plasma Science 32:2026-2031). UV lightranges from UVA (400-315 nm), also called long wave or ‘blacklight’; UVB(315-280 nm), also called medium wave; and UVC (<280 nm), also calledshort wave or ‘germicidal’.”

Optionally, a wavelength may be used that completely or partiallyinactivates pathogens but limits damage to surrounding tissue. Forexample, a wavelength of 630 nm partially inhibits growth of Pseudomonasaeruginosa and Escherichia coli (Nussbaum, et al. (2002) J. Clin. LaserMed. Surg. 20:325-333). Similarly, a number of oral bacteria, includingAcinobacillus actinomycetemcomitans, Fusobacterium nucleatum,Porphromonas gingivalis, Pnevotella intermedia, and Streptococcussanguis, may be partially inactivated using a diode 665 laser at 100 mWfor 30 s (energy density 10.6 J/cm²) or 60 s (energy density 21.2 J/cm²)at a distance of 5 mm (Chan, et al. (2003) Lasers Surg. Med. 18:51-55).

Inactivation of bacteria by a diode 665 laser may be enhanced, forexample, by pre-staining the bacteria with methylene blue (Chan, et al.(2003) Lasers Surg. Med. 18:51-55). Similarly, oral bacteria may beinactivated using a He—Ne laser at 30 mW for 30 s (energy density 3.2J/cm²) or 60 s (energy density 6.4 J/cm²) in combination with methyleneblue (Chan, et al. (2003) Lasers Surg. Med. 18:51-55).

Alternatively, a pathogen or pathogens may be inactivated or killed atthe incision site with a form of laser thermal ablation using, forexample, a CO₂ or Nd:YAG laser (Bartels, et al. SPIE Vol 2395:602-606).For example, Staphylococcus aureus may be partially inactivated orkilled using high-power Nd:YAG laser radiation between 50 and 300 W withlaser pulse frequencies of 5 to 30 Hz and pulse energies from 2 to 30 J,resulting in a range of energy densities from 800 to 270 J/cm² (Yeo, etal. (1998) Pure Appl. Opt. 7:643-655). Escherichia coli 0157:H7, forexample, is extremely sensitive to heat with a maximum tolerance ofapproximately 35 degrees centigrade (U.S. Pat. No. 6,030,653).

Pathogens may be inactivated or killed using X-ray and gammaelectromagnetic energy. For example, Escherichia coli 0157:H7,Salmonella, and Campylobacter jejuni may be at least partiallyinactivated or killed using cobalt-60 gamma radiation at doses of 0.5 to3 kGy (Clavero, et al. (1994) Applied Environ. Microbiol. 60:2069-2075).

Alternatively, pathogens may be inactivated or killed using a form ofparticle beam irradiation. For example, Salmonella, Yersinia, andCampylobacter may be at least partially ablated using acceleratedelectrons with doses of irradiation ranging from 1-3 kGy (Sarjeant, etal. (2005) Poult. Sci. 84:955-958). Similarly, Bacillus endospores maybe at least partially ablated using electron beam irradiation with dosesranging from 5 to 40 kGy (Helfinstine, et al. (2005) Applied Environ.Microbiol. 71:7029-7032).

Viruses may be inactivated on a surface using UV irradiation (Tseng &Li, (2007) J. Occup. Envirn. Hyg. 4:400-405). Fungi, for exampleAspergillus flavus and Aspergillus fumigatus, may also be inactivatedusing UV germicidal irradiation at 12-98 mJ/cm² (Green, et al. (2004)Can. J. Microbiol. 50:221-224).

Alternatively, energy may be used that disrupts the function of hemeiron porphyrins associated with iron uptake and utilization,inactivating iron dependent bacteria such as Escherichia coli andSalmonella (U.S. Pat. No. 6,030,653). Pathogens may be inactivated byirradiating the surface with visible and near infrared light havingwavelengths of approximately 465 nm, 600 nm, and 950 nm, respectively.

In some instances, the entirety of the affected tissue may be irradiatedto at least partially inactivate or kill pathogens. Alternatively,focused energy may be directed only to those sites emittingpathogen-associated autofluorescence or fluorescence. A pathogen orpathogens at the site of incision may be inactivated or killed by energyemitted from a device in either the presence or absence of prophylacticantibiotics (Dellinger, et al. (1994) Clin. Infect. Dis. 18:422-427).

There are a number of microbial pathogens of concern during surgicaltreatment that may lead to difficult to treat nosocomial or hospitalacquired infection, including methicillin-resistant Staphylococcusaureus (MRSA), Staphylococcus epidermidis, Streptococcus pyogenes,Pseudomonas aeruginosa, vancomycin-resistant Enterococci (VRE), extendedspectrum b-lactamase-producing bacteria (ESBL), multi-drug resistance inMycobacterium tuberculosis (MDRTB) strains as well as multi-drugresistant Gram-negative bacteria (Lichtenstern, et al. (2007) Dig. Surg.24: 1-11; NIAID (National Institute of Allergy and Infectious Disease)Profile Fiscal Year 2005, Selected Scientific Areas of Research,Antimicrobial Resistance, pages 52-55).

The Gram-positive bacteria Staphylococcus aureus is a common cause ofsuperficial skin infections such as boils, furuncles, styes, impetigo.S. aureus is also a major cause of nosocomial and community-acquiredinfections, particularly in individuals debilitated by chronic illness,traumatic injury, burns or immunosuppression, as well as a common causeof postoperative infection. The infection may produce abscesses at thestitches or may cause extensive destruction of the incision site.Postoperative infections caused by S. aureus may appear a few days toseveral weeks after an operation but may develop more slowly in anindividual taking antibiotics. Upon bloodstream dissemination or bycontinuous spread, S. aureus can readily survive in various deep tissuesand can cause, among others, abscess formation, osteomyelitis,endocarditis, and sepsis. S. aureus may be detected by autofluorescenceat the incision site using a device emitting electromagnetic energy at awavelength, for example, of 488 nm (Hilton (1998) SPIE 3491:1174-1178).Optionally, S. aureus may be distinguished from, for example,Escherichia coli and Enterococcus faecalis based on emission spectrainduced by excitations at 410-430 nm (Giana, et al. (2003) J. Fluoresc.13:489-493; Ammor (2007) J. Fluoresc. published on-line ahead ofpublication).

S. aureus associated with the incision site may be killed or inactivatedby irradiating the tissue with energy, for example, at a short UV“germicidal” wavelength as described above. Alternatively, S. aureus maybe inactivated using a blue light with a wavelength, for example, of 405nm at doses ranging from 1-20 Jcm⁻² (Guffey, et al. (2006) Photomed.Laser Surg. 24:680-683). Optionally, a blue light may be combined, forexample, with an infrared light at a wavelength of 880 nm to promotetissue repair in combination with bacterial ablation (Guffey, et al.(2006) Photomed. Laser Surg. 24:680-683). In some instances, theentirety of the effected tissue may be irradiated. Alternatively,focused energy may be directed only to those sites emitting S.aureus-associated autofluorescence.

The Gram-negative bacteria Pseudomonas aeruginosa is another commoncause of nosocomial infections, particularly in patients hospitalizedwith cancer, cystic fibrosis, and burns, and has a mortality rate of50%. Other infections caused by Pseudomonas species includeendocarditis, pneumonia, and infections of the urinary tract, centralnervous system, wounds, eyes, ears, skin, and musculoskeletal system. P.aeruginosa is an opportunistic and ubiquitous pathogen with limitedtissue penetration on its own, gaining entry to the host, for example,through burns, wounds, intravenous and urinary catheterization, andsurgical procedures. P. aeruginosa may be detected by autofluorescenceat the incision site using a device emitting electromagnetic energy at awavelength, for example, of 488 nm (Hilton (1998) SPIE 3491:1174-1178).P. aeruginosa contains a pigment called pyocyanin which appears blue invisible light and may also be used for detection.

P. aeruginosa may be killed using a blue light with a wavelength, forexample, of 405 nm at doses ranging from 1-20 Jcm⁻² (Guffey, et al.(2006) Photomed. Laser Surg. 24:680-683). Alternatively, irradiationusing a wavelength, for example, of 630 nm at 1-20 Jcm⁻² may partiallyinactivate P. aeruginosa (Nussbaum, et al. (2002) J. Clin. Laser Med.Surg. 20:325-333).

Example 2

Detection and Ablation of Pathogens Prior to Closing and/or Bandaging aWound

A wound may be screened with a handheld device that detects and ablatespathogens within the open lesion prior to closing (e.g. suturing) and/orbandaging to prevent possible microbial infection. The device emitselectromagnetic energy at wavelengths sufficient to induceautofluorescence of pathogens within the wound. Alternatively, thedevice emits electromagnetic energy at wavelengths sufficient to inducefluorescence of reagents applied to the wound to selectively detectpathogens, such as, for example, a chemical dye or an antibody oraptamer conjugated to a fluorescent tag. Pathogens may include bacteria,fungi and/or viruses. The handheld device detects the autofluorescenceor reagent-induced fluorescence associated with the pathogens and inreal time automatically delivers energy sufficient to ablate or kill thepathogens. Optionally, the handheld device detects the autofluorescence,collects and processes the data, and at the discretion of the user, atrigger mechanism, for example, is used to deliver energy sufficient toat least partially inactivate or ablate the pathogens at the coordinatesassociated with the autofluorescence.

Pathogens commonly associated with wound infections include theGram-positive cocci Streptococcus pyogenes, Enterococcus faecalis, andStaphylococcus aureus, the Gram-negative rods Pseudomonas aeruginosa,Enterobacter species, Escherichia coli, Klebsiella species, and Proteusspecies, the anaerobes Bacteroides and Clostridium, and the fungiCandida and Aspergillus (World Wide Wounds January 2004). Additionalmicrobes of concern include Burcella, which infects cows, sheep, andgoats, and can be transmitted through secretion and excretion to openwounds, Bartonella henselae, which is associated with cats and can cause“cat scratch fever”, and Clostridium tetani which survives for years insoil and animal feces and can cause infection in both superficial woundsand deep in contaminated wounds of individuals not immunized againsttetanus (Park, et al. (2001) J. Bacteriol. 183:5751-5755). In addition,Vibrio vulnificus is an emerging human pathogen which is found primarilyin sea water and can be transmitted into open wounds and cause infection(Oliver, et al. (1986) Applied Environmental Microbiology 52:1209-1211).Among healthy individuals, ingestion of V. vulnificus can causevomiting, diarrhea, and abdominal pain. In immunocompromised persons,particularly those with chronic liver disease, V. vulnificus can invadethe bloodstream through a wound, causing primary septicemia and a 50%mortality rate.

A pathogen or pathogens may be detected at the wound site based onautofluorescence induced by electromagnetic energy at specific ormultiple wavelengths, as described herein. Bartonella henselae, forexample, has weak autofluorescence at an excitation wavelength of 485 nmand emission wavelength of 538 nm (Park, et al. (2001) J. Bacteriol.183:5751-5755). Some strains of V. vulnificus exhibit bioluminescencewith maximal light emission at 483 nm (Oliver, et al. (1986) AppliedEnvironmental Microbiology 52:1209-1211).

Alternatively, pathogens may be detected at the wound site based onaddition of an agent or agents that fluoresces and binds selectively tothe pathogen, allowing for detection and subsequent ablation of thepathogen. For example, a fluorescent stain such as BacLight™ Green orBacLight™ Red bacterial stain (absorption/emission: 480/516 and 581/644,respectively) may be used to detect, for example, Staphylococcus aureusand Escherichia coli (Invitrogen, Carlsbad, Calif.). S. aureus may alsobe detected at the wound site based on binding of immunoglobulins to thebacterial cell wall. Protein A on the surface of S. aureus readily bindsthe IgG class of immunoglobulins (Hjelm, et al. (1972) FEBS Lett.28:73-76). To detect S. aureus, the incision site may be briefly sprayedwith a sterile saline solution containing, for example, an IgG antibodyconjugated to a fluorescent tag, for example FITC, Rhodamine, or Cy3,and rinsed. The fluorescence is detected by the handheld device. Inresponse, energy is emitted specifically to the fluorescing site and thebacteria are killed.

Alternatively, pathogens may be detected at the wound site usingfluorescently labeled antibodies. For example, Streptococcus pyogenses,one of the main pathogens associated with necrotizing fasciitis, may bedetected using antibodies from commercial sources (e.g. AbD SEROTEC,Oxford, UK; Affinity BioReagents, Golden, CO; GeneTex, Inc. San Antonio,Tex.). Antibodies against S. pyogenses may be conjugated, for example,with a fluorescent tag such as the Alexa Fluors, FITC, Oregon Green,Texas Red, Rhodamine, Pacific Blue, Pacific Orange, Cy3, or Cy5 usinglabeling kits available from commercial sources (e.g. Invitrogen,Carlsbad, Calif.; Pierce, Rockford, Ill.). Alternatively, antibodies toS. pyogenses may be labeled with quantum dot nanocrystals using labelingkits from commercial sources (e.g. Invitrogen, Carlsbad, Calif.).Similarly, P. aeruginosa and S. aureus, for example, may be detected atthe wound site using commercially available antibodies tagged with afluorophore (e.g. Accurate Chemical & Scientific Co., Westbury, N.Y.;AbD SEROTEC, Oxford, UK; Cell Sciences Inc., Canton, Mass.).

The fluorescing bacterial stain, immunoglobulin, antibody, or aptamermay be administered to the wound in a sterile solution, rinsed and thewound subsequently screened with the handheld device. The handhelddevice may be placed in close proximity to a wound and emitselectromagnetic energy at wavelengths ranging, for example, from 300 to700 nm to excite autofluorescence of endogenous molecules orfluorescence of a probe associated with the pathogen. The resultingfluorescence is detected by the handheld device which subsequently emitsenergy sufficient to at least partially inactivate or ablate thepathogen. In some instances, the entirety of the effected tissue may beirradiated. Alternatively, focused energy may be directed only to thosesites emitting pathogen-associated autofluorescence or fluorescence.

Autofluorescence may also be used to detect members of the fungi family.For example, Candida albicans irradiated with electromagnetic energy atwavelengths of 465-495 nm autofluoresces at an emission wavelength of515-555 nm (Mateus, et al. (2004) Antimicrobial Agents and Chemotherapy48:3358-3336; Graham (1983) Am. J. Clin. Pathol. 79:231-234). Similarly,Aspergillus niger and Aspergillus versicolor may be detected usingautofluorescence in response to excitation at 450-490 nm and emission at560 nm (Sage, et al. (2006) American Biotechnology Laboratory 24:20-23;Graham (1983) Am. J. Clin. Pathol. 79:231-234). Alternatively, fungi maybe detected in a wound using the non-selective dye, Congo Red, whichfluoresces at excitation maxima of 470 and 546 nm when irradiated withelectromagnetic energy at wavelengths ranging from 450-560 nm (Slifkin,et al. (1988) J. Clin. Microbiol. 26:827-830).

A pathogen or pathogens at the wound site may be inactivated or killedby energy emitted from a handheld device in response to detection of thepathogen or pathogens by autofluorescence using the same handhelddevice. Energy in the form of UV irradiation may be used to at leastpartially inactivate or kill a pathogen or pathogens as describedherein. Alternatively, a pathogen, for example Escherichia coli, may beat least partially inactivated or killed at a wound site in response tofluence doses ranging from 130-260 J/cm² using a 810 nm diode laser(Jawhara, et al (2006) Lasers Med. Sci. 21:153-159). Alternatively, apathogen or pathogens may be at least partially inactivated or killed atthe wound site with a form of laser thermal ablation using energyemitted, for example, from a CO₂ (10,600 nm) or a Nd:YAG (1064 nm) laser(Bartels, et al. SPIE Vol 2395:602-606). For example, Staphylococcusepidermidis, a common skin bacteria, may be killed using pulsedradiation from a Nd:YAG laser with an exposure of 1000-2000 J/cm²(Gronqvist, et al. (2000) Lasers Surg. Med. 27:336-340). Alternatively,a pathogen at a wound site may be at least partially inactivated orkilled using electron beam or x-ray or gamma irradiation as describedherein.

Optionally, energy emitted from the handheld device may be combined witha photosensitive agent applied directly to the wound (Maisch (2007)Lasers Med. Sci. 22:83-91; Jori, et al. (2006) Lasers Surg. Med.38:468-481). As such, the photosensitive agent may be administered tothe wound in a sterile solution, allowed to incubate for a certaininterval, for example 1-30 minutes, rinsed and subsequently screenedwith the handheld device. The wound may be irradiated by the handhelddevice first with wavelengths sufficient to detect the photosensitiveagent and second with energy sufficient to at least partially inactivateor kill the pathogens. For example, Staphylococcus aureus andPseudomonas aeruginosa may be inactivated using either a 0.95-mWhelium-neon laser (632 nm) or a 5-mW indium-gallium-aluminum-phosphatelaser (670 nm) with exposure doses ranging from 0.1 to 10.0 J/cm² incombination with the bacterial sensitizing agent, toluidine blue O,(DeSimone, et al. (1999) Phys. Ther. 79:839-846). Alternatively, a diodelaser with an emission wavelength, for example, of 808 nm may be used incombination with a topically applied fluorescing dye, for example,indocyanine green (ICG), to inactive a pathogen or pathogens (Bartels,et al. SPIE Vol 2395:602-606). ICG may be used to concentrate the diodelaser energy to very specific “stained” areas with minimal damage tosurrounding tissue. Optionally, a polycationic photosensitizerconjugated between, for example, poly-L-lysine and chlorin_(ε6), may betopically applied to a wound and subsequently irradiated with a diodelaser at 665 nm at doses ranging from, for example, 40-160 J/cm² to killbacteria (Hamblin, et al. (2002) Photochem. Photobiol. 75:51-57).Optionally, pathogens in a wound site, such as, for example,Staphylococcus aureus and Staphylococcus epidermidis, may be at leastpartially inactivated using energy from, for example, an argon-ionpumped dye laser (wavelength of 630 nm with total light dose of 180J/cm²) in combination with 5-aminolevulinic acid or Photofrin (Karrer,et al (1999) Lasers Med. Sci. 14:54-61; Nitzan, et al (1999) Lasers Med.Sci. 14:269-277).

Example 3 Detection and Ablation of Pathogens on Oral or Skin Surfaces

An oral cavity or surface of the skin may be screened with a device thatdetects and ablates pathogens associated with plaque and acne,respectively. The device emits electromagnetic energy at wavelengthssufficient to induce autofluorescence of pathogens on the surface.Alternatively, the device emits electromagnetic energy at wavelengthssufficient to cause fluorescence of reagents added to the surface toselectively detect pathogens, such as, for example, a chemical dye or anantibody or aptamer conjugated to a fluorescent tag. Pathogens mayinclude bacteria, fungi and/or viruses. The device detects theautofluorescence or reagent-induced fluorescence associated with thepathogens and in real time automatically delivers energy sufficient toablate or kill the pathogens. Optionally, the device detects theautofluorescence, collects and processes the data, and at the discretionof the physician or other medical practitioner, a trigger mechanism, forexample, is used to deliver energy sufficient to at least partiallyinactivate or ablate the pathogens at the coordinates associated withthe autofluorescence. The device may be handheld, for example, andeither self-contained or connected wirelessly or by wire to optionally apower supply, energy sources, control circuitry, and/or monitor.Alternatively, the device may be a fixed component of, for example, adentist's or doctor's office.

A device emitting energy may be used to detect and ablate the pathogensassociated with dental plaque. For example, pathogens associated withcaries and dental plaques, including Actinomyces odontolyticus,Prevotella intermedia, Porphyromonas gingivalis, Peptostreptococcus,Candida albicans, and Corynebacterium, all autofluoresce red in responseto violet-blue light at a wavelength of 405 nm (van der Veen, et al.(2006) Caries Res. 40:542-545; Koenig, et al. (1994) J. Fluoresc.4:17-40). Similarly, healthy dental tissue may be distinguished fromcarious lesions based on the autofluorescence of the associatedpathogens (Koenig, et al. (1994) J. Fluoresc. 4:17-40). For example,healthy dental tissue irradiated with an excitation wavelength, forexample, of 405 nm may exhibit a broad emission spectra in theshort-wavelength portion of the visible spectrum while fluorescencespectra from a carious lesion may have a maxima in the red spectralregion with a main band at 635 nm, for example (Koenig, et al. (1994) J.Fluoresc. 4:17-40). Once the autofluorescence is detected, energyemitted from the device may be used to at least partially inactivate orkill the fluorescing bacteria in real time using the methods and/ordevices described herein.

A device emitting energy may be used to detect and ablate the pathogensassociated with acne vulgaris. For example, the Gram-positive bacteriaPropionibacterium acnes, which are involved in the pathogenesis of acnevulgaris, may be detected on the surface of the skin usingautofluorescence (Koenig, et al. (1994) J. Fluoresc. 4:17-40; Shalita,et al (2001) SPIE Vol. 4244, p. 61-73). A laser emitting radiation at407 nm, for example, may be used to detect fluorescent spots in thenasal area and in pimples of acne patients. The spots may differ incolor, with their spectrum consisting of three main peaks, at about580-600, 620, and 640 nm, and may be associated with autofluorescenceinduced by endogenous porphyrins such as protoporphyrin andcoproporphyrin (Koenig, et al. (1994) J. Fluoresc. 4:17-40). Once theautofluorescence is detected, energy emitted from the device, forexample, UV radiation, may be used to at least partially inactivate orkill the fluorescing bacteria in real time using the methods describedherein. Alternatively, electromagnetic energy emitted from the device inthe violet-blue range (407-420 nm) may be used to at least partiallyinactivate or kill pathogens associated with acne vulgaris by activatingthe endogenous porphyrins and causing photo-destructive ablation of thebacteria (Shalita, et al (2001) SPIE Vol. 4244, p. 61-73). For example,patients with acne vulgaris may be treated with a 400 w UV-free,enhanced blue (407-420 nm) metal halide lamp producing, for example, 90mW/cm² homogeneous illumination (Shalita, et al (2001) SPIE Vol. 4244,p. 61-73).

Alternatively, a pathogen in the oral cavity or on the surface of theskin may be at least partially inactivated or killed using electron beamor x-ray or gamma irradiation as described herein.

Example 4 Detection and Ablation of Cancer and Cancer Margins

Tissue may be screened with a device that detects and ablates cancerouscells optionally in real time. The device emits electromagnetic energyat wavelengths to induce autofluorescence selected to differentiatebetween normal and cancerous cells. Alternatively, the device emitselectromagnetic energy at wavelengths sufficient to cause fluorescenceof reagents added to the tissue to selectively detect cancerous cells,such as, for example, a photosensitizer, a chemical dye, or an antibodyor aptamer conjugated to a fluorescent tag. Autofluorescence orreagent-induced fluorescence associated with cancerous cells may be usedto detect cancers and to aide in surgical intervention. In addition,autofluorescence or reagent-induced fluorescence associated withcancerous cells may be used to aide a medical practitioner in definingthe margins of a solid tumor to ensure thorough excision of the lesion.

The device detects the autofluorescence or reagent-induced fluorescenceassociated with the cancerous cells and in real time delivers energysufficient to at least partially inactivate or ablate the cancerouscells. Optionally, the device detects the autofluorescence, collects andprocesses the data, and at the discretion of the surgeon or othermedical (or veterinary) practitioner, a trigger mechanism, for example,is used to deliver energy sufficient to at least partially inactivate orablate the cancerous cells at the coordinates associated with theautofluorescence. The device may be handheld, for example, and eitherself-contained or connected wirelessly or by wire to optionally a powersupply, energy sources, control circuitry, and/or monitor.Alternatively, the device may be a fixed component of a surgicaltheater, doctor's office, or other venue for patient treatment.

Electromagnetic energy emitted from a device may be used to induceautofluorescence of a tissue such as, for example, the surface of theskin or the surface of an internal organ exposed during surgery. Thedifferences in the properties of emitted fluorescence may be used todistinguish between normal and pathological tissue. Tissue may beilluminated with electromagnetic energy at specific wavelengths ofultraviolet or visible light, for example. Endogenous fluorophores willabsorb the energy and emit it as fluorescent light at a longerwavelength. Tissue autofluorescence may originate from aromatic aminoacids such as tryptophan, tyrosine, and phenylalanine (excitationwavelengths of 200-340 nm, emission wavelengths of 360-370, 455 nm),from reduced pyridine nucleotides such as nicotinamide adeninedinucleotide (NADH, excitation wavelength of 360 nm, emission wavelengthof 460 nm), from flavins and flavin nucleotides such as riboflavin andflavin mononucleotide (excitation wavelengths of 360 nm, 445-470 nm,emission wavelengths of 440 nm, 520 nm), from structural proteins suchas collagen, and from lipopigments such as ceroid and lipofuscin (Chung,et al. (2005) Current Surgery 62:365-370; DaCosta, et al. (2005) J.Clin. Path. 58:766-774).

Differences in the properties of emitted autofluorescence may be used todistinguish, for example, between normal and cancerous cells and tissuein a variety of epithelial organ systems, including the cervix, colon,bladder, bronchus and oral mucosa (Ann. Surg. Oncol. (2003) 11:65-70;Weingandt, et al. (2002) BJOG 109:947-951; DaCosta, et al. (2005) J.Clin. Path. 58:766-775; Chiyo, et al. (2005) Lung Cancer 48:307-313).For example, changes in autofluorescence emission (350 to 700 nm) ofpremalignant or malignant lesions in the oral cavity relative to normaltissue may be detected using excitation wavelengths of 337 nm, 365 nm,and 410 nm (Gillenwater, et al. (1998) Arch. Otolaryngol. Head NeckSurg. 124:1251-1258). In this instance, the fluorescence intensity ofnormal mucosa may be greater than that of abnormal areas, while theratio of red fluorescence (635 nm) to blue fluorescence (455-490 nm)intensities may be greater in abnormal areas. Autofluorescence may alsobe used to distinguish between normal and cancerous cells innon-epithelial organ systems, such as, for example, between normal whiteand gray matter and cancerous cells in the brain (U.S. Pat. No.6,377,841).

Alternatively, cancerous cells may be detected using electromagneticenergy in combination with a light-activated dye. For example,Photofrin® (Axcan Pharma, Inc.) administered systemically to patientswith cancer in the oral cavity, esophagus or bronchus accumulatespreferentially in cancerous cells. Fluorescence of activated Photofrin®in cancer cells may be measured at 630 nm, for example, in response toexcitation wavelengths of 405 nm and 506 nm 1-50 hours afteradministration (Braichotte, et al. (1995) Cancer 75:2768-2778).

As cancerous cells are identified based on differences inautofluorescence relative to normal cells using the device, the samedevice may be used in real time to ablate the identified cancerouscells. A cancerous cell or cells may be ablated by energy in the form ofhigh-intensity light emitted, for example, by a laser. Lasers arecommonly used to treat superficial cancers, such as basal cell skincancer and the very early stages of some cancers, such as cervical,penile, vaginal, vulvar, and non-small cell lung cancer (National CancerInstitute (2004) Lasers in Cancer Treatment FactSheet). Energy emittedfrom a laser may also be used to relieve certain symptoms associatedwith cancer, such as bleeding or obstruction. For example, a laser maybe used to shrink or destroy a tumor blocking the trachea or theesophagus or to remove polyps or tumors blocking the colon or stomach.

A variety of lasers with varied excitation wavelengths and penetrationpotential may be used to generate electromagnetic energy sufficient toablate a cancer cell or cells (Burr Interventional Technologies forTissue Volume Reduction, October 2004). For example, a cancer cell orcells may be ablated using a CO₂ laser (10,600 nm, 0.1-0.2 mmpenetration depth). Alternatively, cancer cells may be ablated by aYttrium-Aluminium-Garnet (YAG) laser with Neodymium (Nd, 1064 nm or 1320nm, 3-4 mm penetration depth), Erbium (Eb, 2940 nm, with <0.1 mmpenetration depth), or Holmium (Ho, 2070 nm). Alternatively, cancercells may be ablated by diode lasers (600-1600 nm), argon laser (488 nmand 514 nm, 1-1.5 mm penetration depth), or an excimer laser (180-350nm, cell/tissue disintegration). As such, the device may contain one ormore of the lasers described herein as an optical energy source for usein exciting and/or ablating the target tissue.

Alternatively, a cancer cell or cells may be ablated by electromagneticenergy emitted from a laser in combination with a photosensitizing agentin a process termed photodynamic therapy (PDT; National Cancer Institute(2004) Lasers in Cancer Treatment FactSheet). For example, a patient maybe injected with a photosensitizing agent such as, for example,Photofrin or 5-aminolevulinic acid, which after a few days concentratesin the cancerous cells. Electromagnetic energy from, for example, alaser is then used to activate the photosensitizing agent which has asubsequent toxic effect on the cancer cell or cells and results in celldeath.

Alternatively, a cancer cell or cells may be ablated using x-ray energy.X-ray therapy or radiotherapy may be used to treat almost every type ofsolid tumor, including cancers of the brain, breast, cervix, larynx,lung, pancreas, prostate, skin, spine, stomach, uterus, or soft tissuesarcomas (National Cancer Institute (2004) Radiation Therapy for CancerFactSheet). As such, the device may include a standard linearaccelerator that emits X-ray electromagnetic energy at wavelengthssufficient for therapeutic ablation of cancerous cells. Alternatively,the device may contain a miniature X-ray emitter (see e.g. U.S. PatentApplication 2004/218724 A1). Alternatively, the device may containradioisotopes such as cobalt 60, cesium 137, or europium 152, forexample, that emit strong gamma rays and may be used to ablate cancerouscells. Optionally, the device may contain other intrinsicallyradioactive isotope such as those that might be used for brachytherapy,including, for example, iodine 125, iodine 131, strontium 89,phosphorous, palladium, or phosphate (National Cancer Institute (2004)Radiation Therapy for Cancer FactSheet).

Alternatively, a cancer cell or cells may be ablated by using particlebeam energy generated for example by a betatron, cyclotron or microton(Podgorsak, Chapter 5). Alternatively, particle beam energy may begenerated using LINAC (linear accelerator)-based external beamradiotherapy. Medical LINACs accelerate electrons to kinetic energiesfrom 4 to 25 MeV using microwave radiofrequency waves at 10³ to 10⁴ MHz(Podgorsak, Chapter 5). A LINAC may provide X-rays in the lowmegavoltage range (4 to 6 MV). Alternatively, a LINAC may provide bothX-rays and electrons at various megavoltage energies, for example, twophoton energies (6 and 18 MV) and several electron energies (6, 9, 12,16, and 22 MeV; Podgorsak, Chapter 5).

Breast cancer may be detected using a device that emits electromagneticenergy at a wavelength or wavelengths sufficient to induceautofluorescence of malignant tissue. For example, anexcitation-emission matrix of tissue autofluorescence generated usingincremental excitation and emission wavelengths may be used todifferentiate between normal and malignant breast tissue (Ann. Surg.Oncol. (2003) 11:65-70). Breast tissue may be irradiated withelectromagnetic energy at excitation wavelengths of 300 to 460 nm, forexample, in 10 to 20 nm increments and the resulting fluorescenceemission recorded in 5 to 10 nm increments beginning with a wavelength,for example, 10 nm longer than the excitation wavelength, up to, forexample, 600 nm (e.g. 360 to 600 nm for a 350 nm excitation). Anexcitation-emission matrix may be generated using this information andchanges in peaks and valleys of fluorescence intensity may be used todistinguish between normal and malignant tissue. Optionally, a N₂ laseremitting 7 nsec pulses with a repetition rate of 10 Hz, pulse energy of200 μJ, and filtered excitation wavelength of 337 nm may be used todistinguish between autofluorescence of normal and malignant breasttissue (Gupta, et al. (1997) Lasers Surg. Med. 21:417-422).Alternatively, cancerous breast tissue may be ablated using X-rayenergy, for example, from a miniature electron beam-driven X-ray sourceat doses of 5 to 20 Gy (Ross, et al. (2005) Breast Cancer Res.7:110-112). Alternatively, a breast tumor may be at least partiallyablated using electron beam intra-operative radiotherapy with aradiation dose of 17 to 21 Gy (Ross, et al. (2005) Breast Cancer Res.7:110-112).

Squamous intraepithelial lesions of the cervix may be differentiatedfrom normal squamous tissue by autofluorescence using an electromagneticenergy emission wavelength of 460-nm (U.S. Pat. No. 5,623,932).Alternatively, cervical intraepithelial neoplasia may be differentiatedfrom normal tissue by autofluorescence using a frequency tripled Nd:YAGlaser with an excitation wavelength of 355 nm (Nordstrom, et al. (2001)Lasers Surg. Med. 29:118-127). Under these conditions, normal tissue mayhave an autofluorescence maxima (˜460 nm) that is shifted to the leftrelative to neoplastic tissue (˜470 nm) and is of higher intensity,allowing for differentiation between normal and abnormal tissue(Nordstrom, et al. (2001) Lasers Surg. Med. 29:118-127). Optionally,excitation wavelengths between 375 and 440 nm to induce autofluorescencemay be used to distinguish between normal and precancerous lesions ofthe cervix (Weingandt, et al. (2002) BJOG 109:947-951). Alternatively, afluorophore synthesized in the tissue after administration of aprecursor molecule may be used in combination with electromagneticenergy to detect cancerous cells, for example, in the cervix(Andrejevic-Blant, et al. (2004) Lasers Surg. Med. 35:276-283). Forexample, cervical intraepithelial neoplasia may be detected by firstapplying 5-aminolevulinic acid topically to the cervix followed byporphyrin fluorescence spectroscopy (Keefe, et al. (2002) Lasers Surg.Med. 31:289-293). Cervical cancer may be ablated using laser conizationor vaporization using, for example, a CO₂ laser focused to spot size of0.1-0.2 mm with a continuous beam of 40-60 W and a power density of80,000-165,000 W/cm2 (Bekassy, et al. (1997) Lasers Surg. Med.20:461-466) or a garnet (Nd:YAG) laser.

The early stages of melanoma may be detected using a device that emitselectromagnetic energy at incremental wavelengths ranging, for example,from 400-1000 nm using, for example, an acoustic-optic tunable filter(ACTF) in combination with, for example, a white light generated with anKr—Ar laser (Farkas, et al. (2001) Pigment Cell Res. 14:2-8). Spectralimaging of this sort may also be accomplished, for example, usingrotating interference filters, the Fabry-Perot interferometer, liquidcrystal tunable filters (LCTF), gratings or prisms, or Fourier transformspectroscopy (Chung, et al. (2005) Current Surgery 62:365-370). Thereflected light from the potentially cancerous pigmented tissue iscollected at specific wavelengths. A microprocessor may be used togenerate a profile of emission intensity across the electromagneticenergy spectrum. The resulting profile may be compared with that ofnormal pigmented tissue to identify specific areas of dysplasia.Autofluorescence may also be used to differentiate between normal skinand non-melanoma skin lesions. For example, autofluorescence induced byan excitation wavelength of 410 nm may be used to distinguish betweennormal tissue, basal cell carcinoma, squamous cell carcinoma, andactinic keratosis (Panjepour, et al. (2002) Lasers Surg. Med.31:367-373). Optionally, autofluorescence may be used to distinguishbetween sun-exposed and sun-protected areas of skin and may alsoindicate regions of sun damage (Davies, et al. (2001) AppliedSpectroscopy 55:1489-1894). Once the areas of dysplasia or sun damageare identified, the device may emit in real time energy sufficient toablate the abnormal cell or cells. For example, the lesion may beablated using a carbon dioxide laser with a wavelength of 10,600 nm anda power output of 80 W (Gibson, et al. (2004) Br. J. Surg. 91:893-895).

Example 5 Detection and Ablation of Gastrointestinal Pathogens with anUntethered Ingestible Device

An untethered ingestible device may be used to detect and ablategastrointestinal pathogens optionally in real time. The device emitselectromagnetic energy at wavelengths sufficient to induceautofluorescence of pathogens within the gastrointestinal tract.Alternatively, the device emits electromagnetic energy at wavelengthssufficient to induce fluorescence of reagents added to thegastrointestinal tract to selectively detect pathogens, such as, forexample, a chemical dye or an antibody or aptamer conjugated to afluorescent tag. Pathogens may include bacteria, fungi and/or viruses.The untethered ingestible device detects the autofluorescence orreagent-induced fluorescence associated with the pathogens and in realtime delivers energy sufficient to inactivate or ablate the pathogens.Optionally, the untethered ingestible device detects theautofluorescence, wirelessly transmits data to an external source, andat the discretion of the physician or other medical practitioner, atrigger mechanism, for example, is used to deliver energy sufficient toat least partially inactivate or ablate the pathogens at the coordinatesassociated with the autofluorescence.

Pathogens commonly associated with gastrointestinal disorders includebacteria, such as certain strains of Escherichia coli (e.g. Escherichiacoli O157:H7), various strains of Salmonella, Vibrio cholera,Campylobacter, Listeria monocytogenes, shigella, and Helicobacterpylori, viruses such as rotovirus and Calicivirus, and parasites such asGiardia lamblia, Entamoeba histolytica and Cryptosporidium.

A pathogen may be detected in the gastrointestinal tract based onautofluorescence induced, for example, by electromagnetic energy. Ingeneral, pathogens such as bacteria and fungi may be detected byautofluorescence as described herein. For example, Escherichia coliautofluorescence may be detected using excitation wavelengths of 250-400nm and examined at an emission wavelength of 495 nm and higher through,for example, a long pass optical filter (Glazier, et al. (1994) J.Microbiol. Meth. 20:23-27; Hilton, et al. (2000) Proc. SPIE4087:1020-1026). Alternatively, Escherichia coli autofluorescence maximaof 350 nm and 485 nm may be detected following excitation at 290 nm(Cabreda, et al. (2007) J. Fluoresc. 17:171-180). Alternatively,Salmonella as well as Escherichia coli autofluoresce when irradiatedwith electromagnetic energy at a wavelength of 488 nm (Hilton (1998)SPIE 3491:1174-1178). The Coccidia class of bacteria, which aretransmitted through a fecal-oral route via contaminated water and foodand are associated with watery diarrhea, may also be detected based onautofluorescence (Bialek, et al. (2002) Am. J. Trop. Med. Hyg.67:304-305). For example, Isospora belli and Cyclospora fluoresce abluish violet color under UV excitation (365 nm) and fluoresce a brightgreen under violet excitation (405 nm).

A pathogen within the gastrointestinal tract may be inactivated orkilled by energy emitted from an untethered ingestible device inresponse to detection of the pathogen by autofluorescence using the sameuntethered ingestible device. In general, pathogens such as bacteria andfungi may be inactivated or killed by various wavelengths ofelectromagnetic energy as described herein. For example, Escherichiacoli may be partially or completely inactivated, for example, by a 60 sexposure to a UV electromagnetic energy source at wavelengths of 100-280nm (Anderson, et al. (2000) IEEE Transactions on Plasma Science28:83-88). The intestinal parasites Cryptosporidium and Giardia may alsobe at least partially inactivated or killed using UV irradiation from,for example, a mercury arc lamp at a fluence of 40 mJ/cm² (Li, et al.(2007) Appl. Environ. Microbiol. 73:2218-2223). Alternatively,Escherichia coli and Salmonella enteritidis may be inactivated usingpulsed broad-spectrum electromagnetic energy with high UV content from,for example, a Xenon lamp (Anderson, et al. (2000) IEEE Transactions onPlasma Science 28:83-88). In this instance, targeted bacteria aresubjected to 100-1000 pulses of broad-spectrum light with each pulselasting, for example, 85 ns and having, for example, a power output of10 MW. Alternatively, a pathogen within the gastrointestinal tract maybe inactivated or killed by a particle beam, or x-ray, or gamma rayelectromagnetic energy, as described herein.

Helicobacter pylori is a gram-negative bacterium which selectivelycolonizes the stomach and duodenum and is associated with chronicgastritis, gastric ulcer and increased risk for gastric adenocarcinoma.H. pylori may be detected in the antrum of the stomach byautofluorescence using an excitation wavelength, for example, of 405 nm(Hammer-Wilson, et al. (2007) Scand. J. Gastroenterol. 42:941-950). H.pylori naturally accumulates coproporphyrin and protoporphyrin whichsensitize the bacteria to inactivation by visible light at wavelengthsranging from 375 to 425 nm (Hamblin, et al. (2005) Antimicrob. AgentsChemother. 49:2822-2827; U.S. Patent Application 2004/0039232 A1). Assuch, an untethered ingestible device emitting electromagnetic energy asdescribed herein may be used to detect and at least partially inactivateor kill H. pylori in the gastrointestinal tract.

The untethered ingestible device may transit through thegastrointestinal tract by natural peristalsis after ingestion. Transittimes may vary depending, for example, on the time required for gastricemptying and for transit through the small bowel. For example, transittime of an untethered ingestible device out of the stomach may rangefrom 20-160 minutes depending upon, for example, the age of the patientand whether polyethylene glycol (PEG 400) or erythromycin areadministered prior to and following ingestion of the device (Fireman, etal. (2005) World J. Gastroenterol 11:5863-5866). Similarly, transit timethrough the small bowel may range from 220-320 minutes depending, forexample, upon the age of the patient and co-administered agents(Fireman, et al. (2005) World J. Gastroenterol 11:5863-5866).

The untethered ingestible device may be affixed to a specific sitewithin the gastrointestinal tract, for example, by expanding to fill thelumen of the tract (U.S. Patent Application 2007/015621 A1). As such,the untethered ingestible device may be cylindrical in shape with acentral core enabling free flow of fluids within the digestive tract.

Optionally, the untethered ingestible device may contain a means oflocomotion with internal or external control that allows an operator tocontrol movement of the device within the gastrointestinal tract. Thedevice may use a locomotion system based on “inch-worm” motion using,for example, grippers and extensors, rolling tracks, or rolling stents(Rentshcler, et al. (2006) SAGES Meeting; Rentschler, et al. (2007)Surg. Endosc. on-line ahead of publication). Alternatively, the devicemay use a helical wheel configuration on its surface with, for example,two independent motors that control the wheels, providing forward,backward, and turning capacity (see, e.g., Rentshcler, et al. (2006)SAGES Meeting; Rentschler, et al. (2007) Surg. Endosc. on-line ahead ofpublication; U.S. Patent Application 2006/119304 A1). Alternatively, thedevice may use a locomotion system based on wheels or expanding andcontracting components (see, e.g., U.S. Patent Application 2006/119304A1).

Example 6 Detection and Ablation of Pathological Gastrointestinal Tissuewith an Untethered Ingestible Device

An untethered ingestible device may be used to detect and ablatepathological gastrointestinal tissue in real time. The device emitselectromagnetic energy at wavelengths sufficient to induceautofluorescence of pathological tissue within the gastrointestinaltract. Alternatively, the device emits electromagnetic energy atwavelengths sufficient to cause fluorescence of reagents added to thegastrointestinal tract to selectively detect pathological tissue, suchas, for example, a chemical dye or an antibody or aptamer conjugated toa fluorescent tag. Pathological tissue may include, for example, canceror lesions associated with Crohns disease. The untethered ingestibledevice detects the autofluorescence or reagent-induced fluorescenceassociated with the pathological tissue and in real time delivers energysufficient to at least partially ablate the pathological tissue.Optionally, the untethered ingestible device detects theautofluorescence, wirelessly transmits data to an external source, andat the discretion of the physician or other medical practitioner, atrigger mechanism, for example, is used to deliver energy sufficient toat least partially ablate the pathological tissue at coordinatesassociated with the autofluorescence.

For example, changes in autofluorescence emission (350 to 700 nm) ofpremalignant or malignant lesions in the oral cavity relative to normaltissue may be detected using excitation wavelengths of 330, nm, 337 nm,365 nm, and 410 nm (Gillenwater, et al. (1998) Arch. Otolaryngol. HeadNeck Surg. 124:1251-1258; Tsai, et al. (2003) Lasers Surg. Med.33:40-47). In this instance, the fluorescence intensity of normal mucosamay be greater than that of abnormal areas, while the ratio of redfluorescence (635 nm) to blue fluorescence (455-490 nm) intensities maybe greater in abnormal areas. Alternatively, autofluorescence induced byexcitation wavelengths of 365, 385, 405, 420, 435, and 450 nm may becombined with diffuse reflectance spectroscopy to detect pre-malignantand malignant lesions in the oral mucosa (de Veld, et al. (2005) LasersSurg. Med. 36:356-364). Based on the relative autofluorescence, thecancerous cells may be identified and irradiated with electromagneticenergy sufficient to ablate the cell or cells, as described herein.

Autofluorescence may be used to distinguish between normal andneoplastic tissue in patients with Barrett's esophagus (Borovika, et al.(2006) Endoscopy 38:867-872; Pfefer, et al. (2003) Lasers Surg. Med.32:10-16) For example, fluorescence spectra excited at 337 nm and 400 nmmay be used to distinguish between normal and neoplastic tissue (Pfefer,et al. (2003) Lasers Surg. Med. 32:10-16). Alternatively, fluorescencemaxima may be compared at various emission wavelengths, for example,444, 469, 481, 486, 545, 609, and 636 nm following excitation at 337 nmand 400 nm. Autofluorescence may be observed with a long-pass filterwith a cut-off wavelength >470 nm to optimize fluorescence detection andminimize excitation light (Borovika, et al. (2006) Endoscopy38:867-872). Alternatively, adenocarcinoma in patients with Barrett'sesophagus may be detected using electromagnetic energy in combinationwith an agent that concentrates in cancerous cells and that fluorescesupon laser excitation, such as, for example, Photofrin® (von Holstein,et al. (1999) Gut 39:711-716).

Autofluorescence may be used to distinguish between normal, hyperplasticand adenomatous colonic mucosa (DaCosta, et al. (2005) J. Clin. Path.58:766-774; Eker, et al. (1999) Gut 44:511-518). Irradiation of colonmucosa with ultraviolet light or blue light with a wavelength of 488 nm,for example, induces emission of green and red regions ofautofluorescence. In normal tissue, collagen and elastin emit weak greenfluorescence. In hyperplastic tissue or polyps, increased collagenproduces intense green fluorescence. Dysplastic or malignant lesions mayhave enhanced red fluorescence compared with either normal orhyperplastic polyps (DaCosta, et al. (2005) J. Clin. Path. 58:766-774).

An untethered ingestible device emitting electromagnetic energy at awavelength or wavelengths sufficient to induce autofluorescence such asultraviolet or blue light, for example, is used to irradiate the colon.Fluorescence emission is detected at wavelengths of 505-550 nm and >585nm, for example, to detect the green and red autofluorescence,respectively. Alternatively, shifts in the autofluorescence emissionmaxima following excitation at 337 nm may be used to distinguish normalfrom adenomatous tissue (Eker, et al. (1999) Gut 44:511-518).

Optionally, electromagnetic energy may be combined with 5-aminolevulinicacid (ALA) to differentiate between normal colon tissue and adenomatouspolyps (Eker, et al. (1999) Gut 44:511-518). For example, ALA at a doseof 5 mg/kg body weight may be administered orally to patients 2 to 3hours prior to investigation followed by irradiation of the colon tissuewith excitation wavelengths of 337 nm, 405 nm, and 436 nm. Normal versusabnormal tissue may be distinguished based on relative shifts in theemission maxima (Eker, et al. (1999) Gut 44:511-518).

Based on the relative autofluorescence, the cancerous cells areidentified and may be irradiated with energy sufficient to ablate thecell or cells, as described herein. For example, colorectal adenomas maybe ablated using an Nd:YAG (1064 nm) with maximal power output of 100 W(Norberto, et al. (2005) Surg. Endosc. 19:1045-1048). Alternatively,X-ray energy administered at a total dose of 20 Gy may be used to treatcolon cancer (Kosmider, et al. (2007) World J. Gastroenterol.13:3788-3805).

Autofluorescence imaging may be used to detect the severity ofulcerative colitis (Fujiya, et al. (2007) Dig. Endoscopy 19 (Suppl.1):S145-S149). For example, differences in inflammatory state may bedistinguished by autofluorescence, with severely inflamed mucosaassociated with purple autofluorescence, atrophic regenerative mucosaassociated with faint purple autofluorescence with green spots, andnormal mucosa associated with green autofluorescence.

Example 7 Detection and Ablation of Pathogens in a Lumen with anUntethered Device

An untethered device may be used to detect and ablate pathogens within alumen in real time. The device emits electromagnetic energy atwavelengths sufficient to induce autofluorescence of pathogens withinthe lumen. Alternatively, the device emits electromagnetic energy atwavelengths sufficient to cause fluorescence of reagents added to thelumen to selectively detect pathogens, such as, for example, a chemicaldye or an antibody or aptamer conjugated to a fluorescent tag. Pathogensmay include bacteria, fungi and/or viruses. A lumen may include thatassociated with blood vessels, the urogenital tract, and the respiratorytract, for example. The untethered luminal device detects theautofluorescence or reagent-induced fluorescence associated with thepathogens and in real time delivers energy sufficient to inactivate orablate the pathogens. Optionally, the untethered luminal device detectsthe autofluorescence, wirelessly transmits data to an external source,and at the discretion of the physician or other medical practitioner, atrigger mechanism, for example, is used to deliver energy sufficient toat least partially ablate the pathogen at coordinates associated withthe autofluorescence.

An untethered device in the lumen of a blood vessel may be used todetect and ablate pathogens associated with blood infections orsepticemia. Gram-negative enteric bacilli, Staphylococcus aureus, andStreptococcus pneumoniae are the most common pathogens in the UnitedStates associated with micronemia and sepsis. As such, electromagneticenergy emitted from a luminal device may be used to detectautofluorescence associated, for example, with blood borne bacteria asdescribed herein. The pathogens are subsequently ablated using, forexample, UV electromagnetic energy as described herein.

An untethered device in the lumen of a blood vessel may be used todetect and ablate parasites in the blood stream. For example,autofluorescence associated with the food vacuole of the malariaparasite Plasmodium spp. may be used to detect infected erythrocyteswith in the blood stream (Wissing, et al. (2002) J. Biol. Chem.277:37747-37755). As such, an untethered luminal device may induceautofluorescence of parasites at a wavelength, for example, of 488 nm(Wissing, et al. (2002) J. Biol. Chem. 277:37747-37755). Alternatively,erythrocytes infected with Plasmodium spp. may be detected bypre-staining the cells with acridine orange, which when excited at 490nm emits green light at 530 nm (Wissing, et al. (2002) J. Biol. Chem.277:37747-37755). Other nucleic-acid binding dyes may be used for thispurpose including Hoechst 33258, thiazole orange, hydroethidine, andYOYO-1 (Li, et al. (2007) Cytometry 71A:297-307). As such, the dyes bindto parasite DNA in the infected erythrocytes which are otherwise free ofDNA. Erythrocytes autofluoresce upon excitation at a wavelength of 545nm with an emission wavelength of 610 nm associated with the hemeporphyrin (Liu, et al. (2002) J. Cereb. Blood Flow Metab. 22:1222-1230).As such, the untethered luminal device may optionally first identify anerythrocyte based on autofluorescence at one wavelength, followed bydetection of a parasite within the erythrocyte based on autofluorescenceor dye induced fluorescence at a second wavelength. The untetheredluminal device may detect fluorescence associated with infectederythrocytes and in real time emit energy at wavelengths sufficient toat least partially ablate the infected cells.

An untethered luminal device may be used to detect and ablate pathogensassociated with urinary tract infections (UTI), for example, in thelumen of the bladder. For example, Escherichia coli uropathogenicstrains are the most common cause of urinary tract infections (Finer, etal. (2004) Lancet Infect. Dis. 4:631-635). Escherichia coli may bedetected in the bladder, for example, using electromagnetic energy toinduce autofluorescence as described herein. An untethered luminaldevice may be inserted into the bladder via a catheter. Once inserted,the untethered luminal device may scan the internal surface of thebladder with electromagnetic energy sufficient to induceautofluorescence of pathogens. In response to autofluorescence, theuntethered luminal device may emit energy sufficient to at leastpartially inactivate pathogens, as described herein.

Optionally, the untethered luminal device may be affixed to a specificsite within a lumen, for example, by expanding to fill the lumen (see,e.g., U.S. Patent Application 2007/015621 A1). As such, the untetheredluminal device may be cylindrical in shape with a central core enablingfree flow of fluids within the lumen. Alternatively, the untetheredluminal device may be affixed to a specific site within a lumen using,for example, a hook or claw-like structure, an adhesive or glue-likematerial, or suction (see, e.g., U.S. Patent Application 2007/015621A1).

Optionally, the untethered luminal device may contain a means oflocomotion with internal or external control that allows an operator tocontrol movement of the device within the lumen by means describedherein. Alternatively, the untethered luminal device may be controlledby external magnetic energy. For example, an untethered luminal devicein an artery, for example, may be manipulated using a clinical magneticresonance imaging system (see, e.g., Mathieu, et al. Proceedings of the2005 IEEE, Engineering in Medicine and Biology 27^(th) AnnualConference, Shanghai, China, Sep. 1-4, 2005, 4850-4853; Martel, et al.(2007) Applied Physics Letters 90:114105-1-3). As such, the untetheredluminal device may be constructed, at least in part, with ferromagneticmaterial.

Example 9 Detection and Ablation of Pathological Tissue in a Lumen withan Untethered Device

An untethered device may be used to detect and ablate pathologicaltissue or cells within a lumen in real time. The device emitselectromagnetic energy at wavelengths sufficient to induceautofluorescence of pathological tissue within the lumen. Alternatively,the device emits electromagnetic energy at wavelengths sufficient tocause fluorescence of reagents added to the lumen to selectively detectpathological tissue, such as, for example, a chemical dye or an antibodyor aptamer conjugated to a fluorescent tag. Pathological tissue mayinclude cancer, atherosclerosis, and inflammation, for example. A lumenmay include that associated with blood vessels, the urogenital tract,and the respiratory tract, for example. The untethered luminal devicedetects the autofluorescence or reagent-induced fluorescence associatedwith the pathogens and in real time delivers energy sufficient toinactivate or ablate the pathological tissue. Optionally, the untetheredluminal device detects the autofluorescence, wirelessly transmits datato an external source, and at the discretion of the physician or othermedical practitioner, a trigger mechanism, for example, is used todeliver energy sufficient to at least partially ablate the pathologicaltissue at coordinates associated with the autofluorescence.

An untethered device in the lumen of a blood vessel, for example, may beused to detect and ablate tissue and cells associated with, for example,an atherosclerotic plaque. For example, autofluorescence associated withmacrophages in a plaque may be used to characterize an atheroscleroticlesion (Marcu, et al. (2005) Atherosclerosis 181:295-303). Theaccumulation of macrophages in the fibrous cap of an atheroscleroticplaque are indicative of inflammation as well as instability of theplaque. The lumen of a blood vessel may be irradiated, for example, with1 ns pulses of electromagnetic energy at a wavelength of 337 nm. Theresulting autofluorescence may be detected at specific maximawavelengths, for example, 395 nm and 450 nm, or over a range ofwavelengths, for example, from 300-600 nm (Marcu, et al. (2005)Atherosclerosis 181:295-303). Differences in the autofluorescencespectra may be used to differentiate between normal, collagen thick andmacrophage thick plaques (Marcu, et al. (2005) Atherosclerosis181:295-303). Alternatively, the lumen of a blood vessel may beirradiated with electromagnetic energy ranging in wavelength from 350 to390 nm and the resulting autofluorescence detected at criticalwavelengths, for example, of 570, 600, 480, or 500 nm may be sufficientto differentiate between structurally viable tissue and anatherosclerotic plaque (U.S. Pat. No. 5,046,501).

The untethered device may subsequently in real time emit energysufficient to at least partially ablate the atherosclerotic plaque basedon the differential autofluorescence. An eximer laser operating in theultraviolet range may be used to ablate an atherosclerotic plaque(Morguet, et al. (1994) Lasers Surg. Med. 14:238-248). Alternatively,other laser systems may be used to ablate an atherosclerotic plaque,including, for example, a CO2 laser, Nd:YAG laser or an argon laser(Morguet, et al. (1994) Lasers Surg. Med. 14:238-248).

An untethered device in the lumen of a blood vessel, for example, may beused to detect and ablate cells associated with, for example, ahematological form of cancer. For example, leukemia is characterized byan increase in immature lymphoblasts in circulation. These cells mayhave a distinct autofluorescence relative to normal lymphocytes. Assuch, fluorescence associated with the lymphoblasts may be detected andthe cells subsequently ablated using the methods described herein.

An untethered device in the lumen of a blood vessel may be used todetect and ablate cells that have migrated from a solid tumor and are onroute to metastasis elsewhere in the body. These cells may be identifiedusing the untethered device to generate and detect autofluorescence.Alternatively, these cells may be identified using the untethered deviceto induce and detect fluorescence associated with a reagent thatspecifically binds to a cancer cell, such as a fluorescent antibody oraptamer. For example, circulating tumor cells associated with breastcancer may be detected using a fluorescently tagged antibody or aptamerto a tumor specific cell-surface antigen such as, for example, theHer2/Neu epidermal growth factor receptor (Gilbey, et al. (2004) J.Clin. Pathol. 57:903-911). Patients with increased breast epithelialcells in circulation have a higher rate of metastasis and pooreroutcome. As such, fluorescence associated with the breast cancer cellmay be detected and the cell subsequently ablated by the untetheredluminal device using the methods described herein.

Example 10 Detection and Ablation of Pathogens in a Lumen with aTethered Device

A tethered device may be used to detect and ablate pathogens within alumen in real time. The device emits electromagnetic energy atwavelengths sufficient to induce autofluorescence of pathogens withinthe lumen. Alternatively, the device emits electromagnetic energy atwavelengths sufficient to cause fluorescence of reagents added to thelumen to selectively detect pathogens, such as, for example, a chemicaldye or an antibody or aptamer conjugated to a fluorescent tag. Pathogensmay include bacteria, fungi and/or viruses. A lumen may include thatassociated with blood vessels, gastrointestinal tract, the urogenitaltract, or the respiratory tract, for example. The tethered luminaldevice detects the autofluorescence or reagent-induced fluorescenceassociated with the pathogens and in real time delivers energysufficient to inactivate or ablate the pathogens.

A tethered device in the lumen of a blood vessel, for example, may beused to detect and ablate pathogens in the blood such as thoseassociated with septicemia and malaria using electromagnetic energy, asdescribed herein.

A tethered device in the lumen of the lung, for example, may be used todetect and ablate pathogens associated with bronchial infections, suchas bronchitis, pneumonia, and tuberculosis. Streptococcus pneumoniae isthe most common cause of community-acquired pneumonias whereasPseudomonas aeruginosa, Escherichia coli, Enterobacter, Proteus, andKlebsiella are commonly associated with nosocomial-acquired pneumonia.Although the incidence of tuberculosis is low in industrializedcountries, M tuberculosis infections still continue to be a significantpublic health problem in the United States, particularly amongimmigrants from developing countries, intravenous drug abusers, patientsinfected with human immunodeficiency virus (HIV), and theinstitutionalized elderly. Autofluorescence induced by electromagneticenergy may be used to detect various bacterial pathogens, as describedherein. A tethered device may be inserted into the lung comparable, forexample, to a bronchoscope, and used to detect pathogens. In response toautofluorescence, the same tethered device may emit in real time energysufficient to at least partially inactivate pathogens, as describedherein.

Example 11 Detection and Ablation of Pathological Tissue in a Lumen withTethered Device

A tethered device may be used to detect and ablate pathological tissueor cells within a lumen in real time. The device emits electromagneticenergy at wavelengths sufficient to induce autofluorescence ofpathological tissue within the lumen. Alternatively, the device emitselectromagnetic energy at wavelengths sufficient to cause fluorescenceof reagents added to the lumen to selectively detect pathologicaltissue, such as, for example, a chemical dye or an antibody or aptamerconjugated to a fluorescent tag. Pathological tissue may include cancer,atherosclerosis, and inflammation, for example. A lumen may includethose associated with blood vessels, the urogenital tract, thegastrointestinal tract, or the respiratory tract, for example. Thetethered luminal device detects the autofluorescence or reagent-inducedfluorescence associated with the pathological tissue and in real timeautomatically delivers energy sufficient to at least partially ablatethe pathological tissue.

Autofluorescence induced by an optical energy source may be used todetect pathological tissue as described herein. Alternatively,fluorescence associated with a selective marker may be induced by anoptical energy source to detect pathological tissue as described herein.A tethered device that emits optical energy to induce autofluorescenceof pathological tissue may be configured, for example, like an endoscope(see, e.g., U.S. Pat. No. 5,507,287; U.S. Pat. No. 5,590,660; U.S. Pat.No. 5,647,368; U.S. Pat. No. 5,769,792; U.S. Pat. No. 6,061,591; U.S.Pat. No. 6,123,719; U.S. Pat. No. 6,462,770B1). As such, a flexibleoptical tube sufficiently small enough to be inserted into a lumen maybe attached to an optical energy source that emits wavelengthssufficient to induce autofluorescence such as for example, a nitrogenlaser. The same flexible tube may transmit the emitted autofluorescenceback to a CCD camera and control circuitry. Immediately upon receivingthe emitted autofluorescence indicative of pathological tissue, a secondemission of energy, from for example an Nd:YAG laser, is released to atleast partially ablate the pathological tissue. Alternatively, the headof the flexible tube may contain a photodiode array sensor that directlydetects the autofluorescence and triggers a second emission of energysufficient to at least partially ablate the pathological tissue.Alternatively, the head of the flexible tube may contain shielded gammaemitting isotopes that exposure the tissue to radiation in real time inresponse to the detected autofluorescence.

A tethered device in the lumen of a blood vessel, for example, may beused to detect and ablate pathological tissue, for example,atherosclerotic plaques or circulating cancer cells as described herein.

Autofluorescence in combination with reflected light may be used todifferentiate between normal, inflamed and pre-invasive lesions in thelung (Chiyo, et al. (2005) Lung Cancer 48:307-313; Gabrecht, et al.(2007) SPIE-OSA Vol. 6628, 66208C-1-8; U.S. Pat. No. 5,507,287). Forexample, bronchial tissue may be irradiated with excitation wavelengthsof 395-445 nm and autofluorescence detected at wavelengths of 490-690nm. Simultaneously or subsequently, reflected light at 550 nm (green)and at 610 nm (red) may be collected and combined with theautofluorescence data to form a composite image. As such, the ratios ofgreen/red and green/autofluorescence may be greater in squamousdysplasia relative to inflamed lung tissue associated with bronchitis,allowing for differentiation between these two disease states (Chiyo, etal. (2005) Lung Cancer 48:307-313). Based on the relativeautofluorescence detected, the tethered device emits energy sufficientto at least partially ablate the cancerous tissue. For example,electromagnetic energy sufficient to ablate cancerous cells in the lungmay be generated by a Neodynium YAG laser (1064 nm) with power output upto 100 W and tissue penetration of 1-5 mm (Hansen, et al. (2006) Minim.Invasive Ther. Allied Technol. 15:4-8).

Example 12 An Apparatus for Detection and Ablation of Pathogens andPathological Tissue

FIG. 26, FIG. 27, and FIG. 28 show illustrative configurations ofhandheld versions of an apparatus 100 of FIG. 1. for the detection andablation of pathogens and pathological tissue.

FIG. 26 shows an illustrative configuration of a handheld device 2000which is completely self-contained and easily held in the hand of theuser 2001. The user 2001 may be, for example, a surgeon or other medicalpractitioner and/or a veterinarian, using the handheld device 2000, forexample, in a surgical theater, a hospital emergency room, a doctor,dentist, veterinary, or nurse practitioner's office. Alternatively, theuser 2001 may be an emergency responder, using the hand held device2000, for example, out in the field at the site of an accident or on thebattlefield. The user 2001 may hold the handheld device 2000 inproximity to a lesion or lesions 2002 on a patient 2003. The lesion 2002may be a surgical incision or a wound. A wound, for example, may be anabrasion, a burn, a puncture, or a deep gouge. Alternatively, the lesion2002 may be on the surface of the skin or the surface of the oralcavity. The user 2001 turns on the handheld device 2000 using an on/offswitch 2004. Optionally, the user 2001 may use a button 2005 on thehandheld device 2000 to activate or enable a beam of energy 2006(optionally the same as 110). The user 2001 activates a beam of energy2006 in proximity to the lesion 2002 to detect and ablate pathogens andpathological tissue.

FIG. 27 shows an illustrative configuration of a handheld device 2007which is held in the hand of the user 2001 and is optionally wirelesslyconnected to optional external control circuitry 2008. Optionally, thehandheld device 2007 is connected via a wire 2009 to external controlcircuitry 2008 or an external power source 2010, or both. The user 2001activates a beam of energy 2006 in proximity to the lesion 2002 todetect and ablate pathogens and pathological tissue.

FIG. 28 shows an illustrative configuration of a handheld device 2011which is held in the hand of the user 2001, and is used in conjunctionwith targeting aids 2014 surrounding the lesion 2002 on the surface ofthe patient 2003. The targeting aids 2014 are used, for example, toregister the position of autofluorescence associated with pathogens orpathological tissue within the lesion 2002 with respect to the surfaceof the patient 2003. As such, the user 2001 may screen the entire lesion2002, noting the position of possible pathogens or pathological tissue.The user 2001 may subsequently return to specific regions of concern andat the discretion of the user 2001, manually initiate ablation using,for example, a trigger 2012. The handheld device 2011 may include amonitor 2013 that allows the user 2001 to observe the autofluorescenceemitted from the lesion 2002 in real time and/or to observe a targetingbeam of optionally visual light indicating the location of emittedenergy for excitation and/or ablation.

Alternatively, the handheld device may be connected to an externaldisplay device and control circuitry 2008 as described in FIG. 27. Theuser 2001 places at least three targeting aids around the lesion 2002 onthe patient 2003. The user 2001 scans the surface of the lesion 2002with the handheld device 2011 and data is collected regarding theposition of autofluorescence associated with a pathogen or pathologicaltissue. The user 2001 may analyze the accumulated data and at thediscretion of the user 2001, return to specific regions of the lesion2002 and use the trigger 2012 to initiate or enable irradiation with abeam of energy 2006 to ablate pathogens or pathological tissue.Alternatively, the targeting aids 2014 may be placed on fixed surfaces,for example, of the examination room. As such, the extremity with thelesion 2002 is immobilized to an examining surface, for example, to aidein location registration.

FIG. 29 shows an illustrative configuration of a stationary version ofthe apparatus 100 for the real time detection and ablation of pathogensand pathological tissue. The stationary device 2015 may be a componentof a room 2016 that is, for example, part of a surgical theater, animaging and treatment facility, or a doctor's or dentist's orveterinarian's office. The stationary device 2015 may be used inconjunction with targeting aids 2014 placed at various locations aroundthe room 2016. In the example shown in FIG. 29, the targeting aids 2014are affixed to the walls 2017 of the room 2016. Alternatively, thetargeting aids 2014 may be affixed to the ceiling, to the floor or toobjects within the room, or a combination thereof.

The user 2001 may control the stationary device 2015 using controlcircuitry 2008 optionally in an auxiliary room 2018 optionally visuallyconnected to the main room 2016 by a window or other viewing means, forexample. The room 2016 may also contain a table 2019 upon which there isoptionally a sliding platform 2020 for moving the patient 2003 intoposition relative to the stationary device 2015. The sliding platform2020 may also have strategically placed targeting aids 2014.Alternatively, targeting aids 2014 may be placed on the patient 2003 inproximity to the lesion 2002 as described herein. In an alternativeconfiguration, the patient 2003 may remain stationary on a table 2019while some component of the stationary device 2015 is moved into theappropriate position relative to the lesion 2002.

The user 2001 may scan a lesion 2002 with the stationary device 2015using a beam of energy 2006 to detect autofluorescence associated withpathogens or pathological tissue. The beam of energy 2006 exciting theautofluorescence associated with the pathogen or pathological tissue maybe emitted, for example, from a mercury arc lamp, a Xenon lamp, a UVeximer, a halogen lamp, a laser or light emitting diode at wavelengthsranging, for example, from 200 nm to 1000 nm. The stationary device 2015may automatically ablate the pathogen or pathological tissue based onthe emitted autofluorescence. Alternatively, data may be collectedregarding the position of autofluorescence associated with a pathogen orpathological tissue. The user 2001 may analyze the accumulated data andat the discretion of the user 2001, return to a specific region of thelesion 2002 based on orientation from the targeting aids 2014 andinstruct the stationary device 2015 to emit a second beam of energy 2006to ablate pathogens or pathological tissue. The second beam of energy2006 may or may not be of the same wavelength and intensity as the firstbeam of energy 2006 used to excite fluorescence. The beam of energy 2006inducing ablation of pathogens or pathological tissue may be an opticalenergy source, such as those described above, an X-ray energy source, aparticle beam energy source, or a combination thereof.

FIG. 30, FIG. 31, and FIG. 32 show schematic representations ofillustrative configurations of handheld versions of an apparatus 100 forthe detection and ablation of pathogens and pathological tissue.

FIG. 30 shows a schematic representation of an illustrativeconfiguration of a completely self-contained handheld device 2021 forthe detection and ablation of pathogens and pathological tissue. Thehandheld device 2021 contains a power source 2022 which powers thecontrol circuitry 2023, the optical energy source 2024, and othercomponents of the device 2021. The optical energy source 2024 may be,for example, a mercury arc lamp, a Xenon lamp, a UV eximer, a halogenlamp, a nitrogen laser or a laser diode. The electromagnetic energy 2029emitted from the optical energy source 2024 may pass through a filter2025 that allows for emission of specific wavelengths appropriate forinducing autofluorescence of pathogens or pathological tissue asdescribed herein. The electromagnetic energy 2029 may pass through alens 2026 to focus the energy and optionally through a chromatic beamsplitter 2027. The electromagnetic energy 2029 hits the lesion 2002resulting in emission of autofluorescence 2030. The autofluorescence2030 is detected by a sensor 2028 and as a result a second wave ofelectromagnetic energy 2029 is emitted in real time from the opticalenergy source 2024 at a wavelength and intensity sufficient to ablatethe detected pathogen or pathological tissue as described herein.

FIG. 31 shows a schematic representation of an illustrativeconfiguration of a handheld device 2031 in which separate energy sourcesare optionally used for detection and ablation of pathogens orpathological tissue. The handheld device 2031 may be powered by aninternal power supply 2022. Optionally, the handheld device may beconnected to an external power supply. The handheld device 2031 may becontrolled by internal control circuitry 2023. Optionally, the handhelddevice 2031 may be connected either with or without wires to externalcontrol circuitry. The handheld device 2031 contains at least oneoptical energy source 2032. The handheld device 2031 may also contain aleast one additional energy source 2033 for the ablation of pathogens orpathological tissue. The energy source 2033 may be an optical energysource, an X-ray source, or a particle beam source, or a combinationthereof.

Electromagnetic energy 2029 emitted from the optical energy source 2032may pass through a filter 2025 that allows for emission of specificwavelengths appropriate for inducing autofluorescence of pathogens orpathological tissue as described herein. The electromagnetic energy 2029may pass through a lens 2026, a series of beam splitters 2027, andthrough a final lens 2026 prior to hitting the lesion 2002. Theautofluorescence 2030 emitted by pathogens or pathological tissue in thelesion 2002 is detected by the sensor 2028. As a result, a second beamof electromagnetic energy 2029 may be emitted from the first opticalenergy source 2032. Alternatively, a second beam of energy 2034 may beemitted from the second energy source 2033 which is a level of energysufficient to ablate a pathogen or pathological tissue as describedherein. The ablation energy may pass through portions of the same beampath, or may use a fully or partially dedicated beam path.

FIG. 32 shows a schematic representation of an illustrativeconfiguration of a handheld device 2035 in which multiple energy sourcesare optionally used for position, detection and ablation of pathogens orpathological tissue. As shown in FIG. 32A, the handheld device 2035 mayinclude a monitor 2036 for observing the autofluorescence associatedwith a pathogen or a pathological tissue. Optionally, the handhelddevice 2035 may be connected with or without wires to an externaldisplay device. The handheld device 2035 may include a control panel2037 allowing for entry of commands by the user. Optionally, thehandheld device 2035 may be connected with or without wires to anexternal control panel associated, for example, with a computer. Thehandheld device may be turned on and off via a switch 2004.

As shown in FIG. 32B, the handheld device 2035 may be powered by aninternal power supply 2022. Optionally, the handheld device may beconnected to an external power supply. The handheld device 2035 may becontrolled by internal control circuitry 2023. Optionally, the handhelddevice 2035 may be connected either with or without wires to externalcontrol circuitry. The handheld device 2035 contains at least oneoptical energy source 2032. The handheld device 2035 may also contain atleast two additional energy sources 2033 for the ablation of pathogensor pathological tissue. The energy source 2033 may be an optical energysource, an X-ray source, or a particle beam source, or a combinationthereof. The handheld device 2035 may also contain at least onetargeting energy source 2038 for positioning the autofluorescenceassociated with a pathogen or pathological tissue relative to one ormore targeting sensors, as described herein.

Energy emitted from the optical energy source 2032 may pass through afilter/focus unit 2039 that allows for emission of specific wavelengthsappropriate for inducing autofluorescence of pathogens or pathologicaltissue as described herein. The autofluorescence emitted by pathogens orpathological tissue in a lesion is detected by the sensor 2028. Theposition of the autofluorescence in the lesion may be determined withthe aide of the targeting energy source 2038 and targeting sensorspositioned, for example, on the surface of the patient in proximity tothe lesion or on various surfaces in a room or a combination thereof asdescribed herein. After the autofluorescence is detected, a second beamof electromagnetic energy may be emitted from the first optical energysource 2032. Alternatively, a second beam of energy may be emitted fromthe second or third energy source 2033 at a level of energy sufficientto ablate a pathogen or pathological tissue as described herein.

As shown in FIG. 32C, energy emitted from or detected by the device 2035passes through one or more openings 2040 at the bottom of the device2035.

FIG. 33 and FIG. 34 show illustrative configurations of untetheredversions of a device 200, 300 and/or 400 for the detection and ablationof pathogens and pathological tissue in the lumen, for example, of ablood vessel.

FIG. 33 shows an illustrative configuration of an untethered device 2041for the detection and ablation of pathogens and pathological tissue inthe lumen 2042 of a blood vessel, for example. Alternatively, theuntethered device 2041 may be used in other lumens including thoseassociated with the gastrointestinal tract, the respiratory tract, andthe urogenital tract, for example. In this configuration, the untethereddevice 2041 may be a hollow cylinder that when placed in a lumen 2042allows for the flow of fluid and cells 2043 through the central core2045 of the cylinder. The hollow cylinder contains a detection andablation unit 2047, which optionally contains a power source, controlcircuitry, one or more energy sources, and a sensor. Control of thedevice may be completely self-contained or controlled wirelessly by anexternal user.

As normal cells 2043 and abnormal cells 2044 pass through the centralcore 2045 of the untethered device 2041, the detection and ablation unit2047 detects autofluorescence associated with the abnormal cells 2044and in real time ablates the abnormal cells 2044. Abnormal cells 2044may be, for example, pathogens, pathological cells or cancerous cells asdescribed herein. The untethered device 2041 may be reversibly fixed ina specific region of the lumen by virtue of inflatable pouches 2046 orother means.

FIG. 34 shows an illustrative configuration of an untethered device 2048for the detection and ablation of pathogens and pathological tissue inthe lumen 2042, for example, of a blood vessel. Alternatively, theuntethered device 2048 may be used in other lumens including thoseassociated with the gastrointestinal tract, the respiratory tract, andthe urogenital tract, for example. In this configuration, the untethereddevice 2048 may be fixed to the surface of a lumen by virtue of a hook2049 which at the appropriate time and location latches on to thesurface of the lumen. Control of the untethered device 2048 may becompletely self-contained or controlled wirelessly by an external user.The untethered device 2048 may sit on the surface of a lumen and monitorthe flow of fluid and normal cells 2043 and abnormal cells 2044. Theuntethered device 2048 emits a beam of energy 2006 which detectsabnormal cells 2044 based on autofluorescence and in real time ablatesthe abnormal cells.

FIG. 35, FIG. 36, and FIG. 37 show illustrative configurations ofuntethered versions of an apparatus 100 with controlled locomotion forthe detection and ablation of pathogens and pathological tissue in alumen associated with, for example, the circulatory system, thegastrointestinal tract, the respiratory tract, or the urogenital tract.

FIG. 35 shows an illustrative configuration of an untethered device 2050with controlled locomotion for the detection and ablation of pathogensand pathological tissue in a lumen 2042. In this configuration, theuntethered device 2050 is a hollow cylinder and has two or morecontrollable wheels 2051 that allow the device to move along the surfaceof a lumen. Control of the movement of the untethered device 2050 may becompletely self-contained or controlled wirelessly by an external user.The hollow cylinder contains a detection and ablation unit 2047, whichoptionally contains a power source, control circuitry, one or moreenergy sources, and a sensor. As the untethered device moves along thesurface of a lumen, a beam of energy 2006 is emitted towards thesurface, for example, scanning for autofluorescence associated with apathogen or pathological tissue. Once autofluorescence is detected, theuntethered device 2050 emits a beam of energy 2006 from the detectionand ablation unit 2047 sufficient to ablate the pathogen or pathologicaltissue.

FIG. 36 shows an illustrative configuration of an untethered device 2052with controlled locomotion for the detection and ablation of pathogensand pathological tissue in a lumen 2042. In the configuration shown, theuntethered device 2052 is a sphere. Optionally, the untethered device2052 may be any configuration that is compatible with housing thecomponents necessary for detection and ablation of pathogens orpathological tissue in a lumen 2042. The untethered device 2052 has twopropellers 2053 mounted on the top and on the side of the sphere toallow the controlled movement of the device in all directions.Optionally, more or less propellers 2053 may be mounted on the device.Optionally, the one or more propellers 2053 may be mounted in differentlocations on the device. Control of the movement of the untethereddevice 2052 may be completely self-contained or controlled wirelessly byan external user. As shown, the untethered device 2052 contains anenergy source 2054, control circuitry, 2055, a sensor 2056, and a powersource 2057. The energy source 2054 may be an optical energy source, anx-ray energy source, a particle beam energy source, or a combinationthereof. The untethered device 2052 moves through a lumen 2042 scanningthe surface of the lumen or cells flowing in the lumen withelectromagnetic energy 2029 (optionally the same as 111) sufficient toinduce autofluorescence associated with a pathogen or pathological cellor tissue. Once autofluorescence is detected by the sensor 2056, theuntethered device 2052 emits energy sufficient to ablate the pathogen orpathological tissue.

FIG. 37 shows an illustrative configuration of an untethered device 2058with controlled locomotion for the detection and ablation of pathogensand pathological tissue in a lumen 2042. In this configuration, the twohalves of the untethered device 2058 have grooves 2059 cut in oppositedirections. The two halves of the untethered device 2058 rotateindependently in opposite directions. Control of the movement of theuntethered device 2058 may be completely self-contained or controlledwirelessly by an external user. Each half of the untethered device mayhave the independent capability of emitting and detecting a beam ofenergy 2006 sufficient to detect and ablate pathogens or pathologicaltissue.

FIG. 38 and FIG. 39 show illustrative configurations of untetheredversions of an apparatus 100 with random movement for the detection andablation of pathogens and pathological tissue in a lumen associatedwith, for example, the circulatory system, the gastrointestinal tract,the respiratory tract, or the urogenital tract.

FIG. 38 shows an illustrative configuration of an untethered device 2060with random movement for the detection and ablation of pathogens andpathological tissue in a lumen. In this configuration, the untethereddevice 2060 is a sphere. Optionally, the untethered device 2060 may beany configuration that is compatible with housing the componentsnecessary for detection and ablation of pathogens or pathological tissuein a lumen 2042. The untethered device 2060 has one or more controllablearms 2061 attached to the surface. A paddle 2062 is attached to the endof each controllable arm 2061. The one or more arms 2061 may move invaried directions relative to the surface of the untethered device andas such, randomly turn the untethered device 2060. Control of themovement of the arms 2061 of the untethered device 2060 may becompletely self-contained or controlled wirelessly by an external user.The untethered device 2060 randomly rotates based on the motion of thearms 2061 and associated paddles 2062, scanning the surface of a lumen2042 with a beam of energy 2006 sufficient to induce autofluorescence.Once autofluorescence associated with a pathogen or pathological tissueis detected, the untethered device 2060 emits energy sufficient toablate the pathogen or pathological tissue.

FIG. 39 shows an illustrative configuration of an untethered device 2063with random movement for the detection and ablation of pathogens andpathological tissue in a lumen. In this configuration, the untethereddevice 2063 is a sphere with two or more tracks 2064 within the interiorof the sphere. Each track 2064 has at least one associated weighted bead2065 that is propelled along the track 2064. Differential movement ofthe weighted beads will cause random rotation of the untethered device2063. The untethered device 2063 randomly rotates based on the motion ofthe two or more weighted beads, scanning the surface of a lumen 2042with a beam of energy 2006, optionally electromagnetic energy 2029 froma detection and ablation unit 2047 sufficient to induceautofluorescence. Once autofluorescence associated with a pathogen orpathological tissue is detected, the untethered device 2063 emits a beamof energy 2006 from the detection and ablation unit 2047 sufficient toablate the pathogen or pathological tissue.

FIG. 40 shows an illustrative configuration of an untethered ingestibledevice 2066 for the detection and ablation of pathogens and pathologicaltissue in the lumen of the gastrointestinal tract 2067. In theconfiguration shown, the untethered ingestible device is a sphere withmultiple openings 2068 covering the surface of the sphere. The multipleopenings 2068 may emit electromagnetic energy 2029 sufficient to induceautofluorescence of a pathogen or pathological tissue and/or pathogencell death. The emitted autofluorescence 2070 induced by theelectromagnetic energy 2029 is detected through one or more of themultiple openings 2068. Once autofluorescence associated with a pathogenor pathological tissue is detected, the untethered ingestible device2066 emits energy sufficient to ablate the pathogen or pathologicaltissue.

In one aspect, the disclosure is drawn to systems implementationsincluding methods, computer programs, and systems for controllingoptionally the detection and ablation and/or movement of targetsoptionally at least partially based on a fluorescent response. One ormore of these systems implementations may be used as part of one or moremethods for optionally detecting and ablating one or more targetsoptionally at least partially based on a fluorescent response, and/orimplemented on one or more apparatus 100 and/or 500 and/or devices 200,300, and/or 400 optionally configured to detect and/or to ablate one ormore target cells. One or more of the operations, computer programs,and/or systems implementations described in association with one or moreembodiments are envisioned and intended to also make part of otherembodiments unless context indicates otherwise.

The operational flows may also be executed in a variety of othercontexts and environments, and or in modified versions of thosedescribed herein. In addition, although some of the operational flowsare presented in sequence, the various operations may be performed invarious repetitions, concurrently, and/or in other orders than thosethat are illustrated. Although several operational flow sequences aredescribed separately herein, these operational flows may be performed insequence, in various repetitions, concurrently, and in a variety oforders not specifically illustrated herein. In addition, one or more ofthe steps described for one or more operational flow sequence may beadded to another flow sequence and/or used to replace one or more stepsin the flow sequence, with or without deletion of one or more steps ofthe flow sequence.

Operations may be performed with respect to a digital representation(e.g. digital data) of, for example, one or more characteristics of afluorescent response, one or more characteristics of excitation energy116, one or more characteristics of ablation energy 117, one or moremovement parameters, and/or one or more targeting parameters. The logicmay accept a digital or analog (for conversion into digital)representation of an input and/or provide a digitally-encodedrepresentation of a graphical illustration, where the input may beimplemented and/or accessed locally or remotely. The logic may provide adigital representation of an output, wherein the output may be sentand/or accessed locally or remotely.

Operations may be performed related to either a local or a remotestorage of the digital data, or to another type of transmission of thedigital data. In addition to inputting, accessing querying, recalling,calculating, determining or otherwise obtaining the digital data,operations may be performed related to storing, assigning, associating,displaying or otherwise archiving the digital data to a memory,including for example, sending, outputting, and/or receiving atransmission of the digital data from (and/or to) a remote memory and/orunit, device, or apparatus. Accordingly, any such operations may involveelements including at least an operator (e.g. human or computer)directing the operation, a transmitting computer, and/or receivingcomputer, and should be understood to occur in the United States as longas at least one of these elements resides in the United States.

FIG. 8 and/or FIG. 9 depict embodiments of an operational flow 600representing illustrative embodiments of operations related to providinga first output to a first energy source in real time, the first outputproviding data associated with at least partial ablation of a target atleast partially based on the first possible dataset. In FIG. 8 and/orFIG. 9, discussion and explanation may be provided with respect to oneor more apparatus 100 and/or 500 and/or device 200, 300 and/or 400 andmethods described herein, and/or with respect to other examples andcontexts.

In some embodiments, one or more methods include receiving a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of a target fluorescent response; andproviding a first output to a first energy source in real time, thefirst output providing data associated with at least partial ablation ofa target at least partially based on the first possible dataset.

In illustrative embodiments, operational flow 600 may be employed in theprocess of target ablation to receive information associated with atarget fluorescent response optionally from one or more apparatus 100and/or 500 and/or devices 200, 300, and/or 400, optionally including,but not limited to, information relating to the wavelength, intensity,strength, directionality, and/or spatial extent of the fluorescentresponse. In illustrative embodiments, operational flow 600 may beemployed in the process of target ablation to analyze informationassociated with a target fluorescent response, optionally from one ormore apparatus 100 and/or 500 and/or devices 200, 300, and/or 400, todetermine one or more characteristics of one or more energy source 110and/or ablation energy 117 associated with at least partially ablatingone or more target.

After a start operation, the operational flow 600 moves to a receivingoperation 160, receiving a first input associated with a first possibledataset, the first possible dataset including data representative of oneor more target fluorescent response. For example, a first input mayinclude, but is not limited to, data representative of one or morewavelengths of excitation energy, direction, pulse time, timing, as wellas detection wavelengths and timing. For example, a first input mayinclude, but is not limited to, a condition, an illness, a cell and/ortissue type under investigation, and/or other disease and/or preventivemedicine information

An optional accessing operation 260 accesses the first possible datasetin response to the first input. For example, data representative of oneor more fluorescent responses, one or more autofluorescent responses,and/or one or more target fluorescent responses may be accessed. Forexample, data representative of background fluorescence, fluorescenttags and/or markers, and/or limits of detection may be accessed.

An optional generating operation 360 generates the first possibledataset in response to the first input. For example, data representativeof one or more target fluorescent response may be generated optionallyby eliminating and/or controlling for endogenous non-target fluorescenceand/or non-specific fluorescence. For example, data representative ofdirection and/or location of a target, the presence or absence of atarget, and/or the risk to non-target cells and tissues of ablation maybe generated.

An optional determining operation 460 determines a graphicalillustration of the first possible dataset. For example, datarepresentative of one or more fluorescent responses, one or moreautofluorescent responses, and/or one or more target fluorescentresponse may be graphically represented. For example, datarepresentative of direction and/or location of a target optionally inrelation to other non-target areas and/or the likelihood of collateraldamage may be graphically represented.

An optional sending operation 560 sends the first output associated withthe first possible dataset. For example, data representative of one ormore fluorescent responses, one or more autofluorescent responses,and/or one or more target fluorescent response may be sent as part ofthe first output. For example, data representative of direction and/orlocation of a target may be sent optionally to an external source and/orto an ablation device.

An optional determining operation 660 determines data representative ofone or more characteristics of excitation energy 116 for inducing thetarget fluorescent response. For example, data representative of one ormore characteristics of excitation energy 116, optionally including, butnot limited to, wavelength, strength, mode, directionality, and/orspatial limitations may be determined.

An optional determining operation 760 determines data representative ofone or more characteristics of ablation energy 117 for at leastpartially ablating a target. For example, data representative of one ormore characteristics of ablation energy 117, optionally including, butnot limited to, wavelength, strength, mode, directionality, and/orspatial limitations may be determined.

An optional operation 860 includes an optional receiving operation 862and an optional determining operation 864. The optional receivingoperation 862 receives a second input associated with a second possibledataset, the second possible dataset including data representative of asecond target fluorescent response following the at least partialablation of the target. The optional determining operation 864determines data representative of one or more characteristics ofablation energy 117 for further ablating a target at least partiallybased on the second possible dataset. For example, data representativeof a second target fluorescent response may include one or morecharacteristics different from the first, previous and/or originaltarget fluorescent response, optionally as a result of the at leastpartial ablation of the target. For example, the one or morecharacteristics may include, but are not limited to, presence, absenceand/or reduction in the target fluorescent response.

An optional operation 960 includes an optional receiving operation 962and an optional determining operation 964. The optional receivingoperation 962 receives a third input associated with a third possibledataset, the third possible dataset including data representative of afluorescent response. The optional determining operation 964 determinesdata representative of one or more characteristics of excitation energy116 for inducing a target fluorescent response at least partially basedon the third possible dataset. For example, data representative of afluorescent response may indicate the presence or absence of a targetfluorescent response.

Then, a providing operation 1060, provides a first output to a firstenergy source in real time, the first output providing data associatedwith at least partial ablation of a target at least partially based onthe first possible dataset. For example, data representative of one ormore characteristics of ablation energy 117, one or more characteristicsof the excitation energy 116, one or more characteristics of thefluorescent response, one or more environmental parameters, and/or oneor more targeting parameters.

FIG. 10 and/or FIG. 11 depict embodiments of an operational flow 700representing illustrative embodiments of operations related to providinga first output to a first energy source in real time, the first outputproviding data representative of one or more ablation characteristicsfor at least partially ablating a target area. In FIG. 10 and/or FIG.11, discussion and explanation may be provided with respect to one ormore apparatus 100 and/or 500 and/or device 200, 300 and/or 400 andmethods described herein, and/or with respect to other examples andcontexts.

In some embodiments, one or more methods include receiving a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of a target fluorescent response;determining data representative of a location of a target area at leastpartially based on the first possible dataset; and providing a firstoutput to a first energy source in real time, the first output providingdata representative of one or more ablation characteristics for at leastpartially ablating the target area.

In illustrative embodiments, operational flow 700 may be employed in theprocess of target ablation to receive information associated with atarget fluorescent response optionally from one or more apparatus 100and/or 500 and/or devices 200, 300, and/or 400, optionally including,but not limited to, information relating to the wavelength, intensity,strength, directionality, and/or spatial extent of the fluorescentresponse. In illustrative embodiments, operational flow 700 may beemployed in the process of target ablation to analyze informationassociated with a target fluorescent response to determine dataassociated with the location of a target and one or more characteristicsof one or more energy source 110 and/or ablation energy 117 associatedwith at least partially ablating one or more target.

After a start operation, the operational flow 700 moves to a receivingoperation 170, receiving a first input associated with a first possibledataset, the first possible dataset including data representative of oneor more target fluorescent response. For example, a first input mayinclude, but is not limited to, data representative of one or morewavelengths of excitation energy, direction, pulse time, timing, as wellas detection wavelengths and timing. For example, a first input mayinclude, but is not limited to, a condition, an illness, a cell and/ortissue type under investigation, and/or other disease and/or preventivemedicine information

An optional accessing operation 270 accesses the first possible datasetin response to the first input. For example, data representative of oneor more fluorescent responses, one or more autofluorescent responses,and/or one or more target fluorescent responses may be accessed. Forexample, data representative of background fluorescence, fluorescenttags and/or markers, and/or limits of detection may be accessed.

An optional generating operation 370 generates the first possibledataset in response to the first input. For example, data representativeof one or more target fluorescent response may be generated optionallyby eliminating and/or controlling for endogenous non-target fluorescenceand/or non-specific fluorescence. For example, data representative ofemissions as a function of wavelength in relation to time and/ordistance may be generated.

An optional determining operation 470 determines a graphicalillustration of the first possible dataset. For example, datarepresentative of one or more fluorescent responses, one or moreautofluorescent responses, and/or one or more target fluorescentresponse may be graphically represented. For example, datarepresentative of possible results associated with (and/or correspondingto) one or more possible ablation parameters, optionally including useof particle beam and/or electromagnetic energy for target ablation,optionally in relation to other non-target areas and/or the likelihoodof collateral damage may be graphically represented.

An optional determining operation 570 determining data representative ofa location of one or more target area at least partially based on thefirst possible dataset. For example, data representative of a locationof one or more target area may include, but is not limited to,direction, spatial extent, environment, and/or depth, optionally inrelation to one or more excitation energy source 116, one or moretargeting energy source 118, and/or one or more ablation energy source117.

An optional sending operation 670 sends the first output associated withthe first possible dataset optionally to the first energy source,optionally the ablation energy source 117. For example, datarepresentative of one or more target fluorescent response, one or morecharacteristics of ablation energy 117, and/or one or more targetingparameters may be sent as part of the first output.

An optional determining operation 770 determines data representative ofone or more characteristics of excitation energy 116 for inducing thetarget fluorescent response. For example, data representative of one ormore characteristics of excitation energy 116, optionally including, butnot limited to, wavelength, strength, mode, directionality, and/orspatial limitations may be determined.

An optional determining operation 870 determines data representative ofone or more characteristics of ablation energy 117 for at leastpartially ablating a target. For example, data representative of one ormore characteristics of ablation energy 117, optionally including, butnot limited to, wavelength, strength, mode, directionality, and/orspatial limitations may be determined.

An optional operation 970 includes an optional receiving operation 972and an optional determining operation 974. The optional receivingoperation 972 receives a second input associated with a second possibledataset, the second possible dataset including data representative of asecond target fluorescent response following the at least partialablation of the target. The optional determining operation 974determines data representative of one or more characteristics ofablation energy 117 for further ablating a target at least partiallybased on the second possible dataset. For example, data representativeof a second target fluorescent response may include one or morecharacteristics different from the first, previous and/or originaltarget fluorescent response, optionally as a result of the at leastpartial ablation of the target. For example, the one or morecharacteristics may include, but are not limited to, presence, absenceand/or extent of reduction in the target fluorescent response.

An optional operation 1070 includes an optional receiving operation 1072and an optional determining operation 1074. The optional receivingoperation 1072 receives a third input associated with a third possibledataset, the third possible dataset including data representative of afluorescent response. The optional determining operation 1074 determinesdata representative of one or more characteristics of excitation energy116 for inducing a target fluorescent response at least partially basedon the third possible dataset. For example, data representative of afluorescent response may indicate the presence, absence, or extent ofreduction of a target fluorescent response.

Then, a providing operation 1170, provides a first output to a firstenergy source in real time, the first output providing datarepresentative of one or more ablation characteristics for at leastpartially ablating the target area. For example, data representative ofone or more characteristics of ablation energy 117, one or morecharacteristics of the excitation energy 116, one or morecharacteristics of the fluorescent response, one or more environmentalparameters, and/or one or more targeting parameters.

FIG. 12 and/or FIG. 13 depict embodiments of an operational flow 800representing illustrative embodiments of operations related to providinga first possible output to a first motive source, the first possibleoutput providing data representative of one or more parametersassociated with movement of an untethered device in a lumen at leastpartially based on the location of the target area. In FIG. 12 and/orFIG. 13, discussion and explanation may be provided with respect to oneor more device 200 and/or 300 and methods described herein, and/or withrespect to other examples and contexts.

In some embodiments, one or more methods include receiving a first inputassociated with a first possible dataset, the first possible datasetincluding data representative of a fluorescent response; determiningdata representative of a location of a target area at least partiallybased on the first possible dataset; and providing a first possibleoutput to a first motive source, the first possible output providingdata representative of one or more parameters associated with movementof an untethered device in a lumen at least partially based on thelocation of the target area.

In illustrative embodiments, operational flow 800 may be employed in theprocess of moving an untethered device in a lumen, optionally associatedwith target ablation, to receive information associated with afluorescent response optionally from one or more devices 200 and/or 300,optionally including, but not limited to, information relating to thewavelength, intensity, strength, directionality, and/or spatial extentof the fluorescent response. In illustrative embodiments, operationalflow 800 may be employed in the process of moving an untethered devicein a lumen to analyze information associated with a target fluorescentresponse to determine data associated with the location of a target andone or more characteristics of one or more power source 140 and/ormotive force, optionally associated with at least partially ablating oneor more target.

After a start operation, the operational flow 800 moves to a receivingoperation 180, receiving a first input associated with a first possibledataset, the first possible dataset including data representative of oneor more fluorescent response. For example, data representative of one ormore fluorescent response may include, but is not limited to, datarepresentative of a target fluorescent response, a non-targetfluorescent response, and/or a autofluorescent response. For example, afirst input may include, but is not limited to, one or morecharacteristics of excitation energy, one or more characteristics oftargeting energy, and/or one or more characteristics of ablation energy.

An optional accessing operation 280 accesses the first possible datasetin response to the first input. For example, data representative of oneor more fluorescent responses, optionally data representative of one ormore target fluorescent response and/or one or more autofluorescentresponse, may be accessed. For example, data representative of thepresence and/or absence of a target fluorescent response and/or presenceor absence of other non-target fluorescent responses may be accessed.

An optional generating operation 380 generates the first possibledataset in response to the first input. For example, data representativeof one or more target fluorescent response may be generated optionallybased on calculations associated with background fluorescent, signal tonoise ratios, non-specific fluorescence, and/or endogenous non-targetautofluoresce. For example, data representative of a location of atarget area determined at least partially based on the fluorescentresponse may also be generated.

An optional determining operation 480 determines a graphicalillustration of the first possible dataset. For example, datarepresentative of one or more target fluorescent response may begraphically represented. For example, data representative of a locationof one or more target area optionally in relation to the current devicelocation may be graphically represented. For example, datarepresentative of one or more parameters associated with the movement ofthe untethered device associated with target ablation and/or targetdetection may be determined and/or generated.

A determining operation 580 determines data representative of a locationof one or more target area at least partially based on the firstpossible dataset. For example, data representative of a location of oneor more target area may include, but is not limited to, direction,spatial extent, environment, and/or depth, optionally in relation to oneor more excitation energy source 116, one or more targeting energysource 118, and/or one or more ablation energy source 117. For example,data representative of a location of one or more target area mayinclude, but is not limited to, one or more characteristics associatedwith movement of an untethered device for target ablation and/or targetdetection.

An optional generating operation 680 generates the first possible outputin response to the first input. For example, a first possible output mayinclude data representative of a location of one or more target area atleast partially based on the first possible dataset. For example, afirst possible output may include, but is not limited to, datarepresentative of a direction of movement, a rate of movement, a speedof movement, a time of movement, a mechanism of movement, and/or a powersource.

An optional sending operation 780 sends the first output associated withthe first possible dataset optionally to a motive source 150 and/or apower source 140. For example, data representative of a direction ofmovement, a rate of movement, a speed of movement, a time of movement, amechanism of movement, and/or a power source may be sent as part of thefirst output.

An optional determining operation 880 determines data representative ofone or more characteristics of excitation energy 116 for inducing thefluorescent response. For example, data representative of one or morecharacteristics of excitation energy 116, optionally including, but notlimited to, wavelength, strength, mode, directionality, and/or spatiallimitations may be determined.

An optional determining operation 980 determines data representative ofone or more characteristics of ablation energy 117 for at leastpartially ablating a target. For example, data representative of one ormore characteristics of ablation energy 117, optionally including, butnot limited to, wavelength, strength, mode, directionality, and/orspatial limitations may be determined.

Then, a providing operation 1080, provides a first possible output to afirst motive source, the first possible output providing datarepresentative of one or more parameters associated with movement of anuntethered device in a lumen at least partially based on the location ofthe target area. For example, data representative of one or morecharacteristics of ablation energy 117, one or more characteristics ofthe excitation energy 116, one or more characteristics of thefluorescent response, one or more environmental parameters, and/or oneor more targeting parameters.

The following include illustrative embodiments of one or more operationsof operational flow 600, operational flow 700 and/or operational flow800.

In illustrative embodiments, a target fluorescent response is optionallyan auto-fluorescent response and/or elicited from one or moreextrinsically provided markers.

In illustrative embodiments, a first input is from a sensor configuredto detect one or more of a target fluorescent response, a fluorescentresponse, and/or an autofluorescent response. In illustrativeembodiments, a first input is from one or more external sources,optionally remotely, programmably, and/or wirelessly received. The oneor more external sources may include, but are not limited to, sensors,control circuitry, databases, and/or user interfaces.

In illustrative embodiments, a first input includes data representativeof one or more measurements of electromagnetic energy. One or moremeasurements of electromagnetic energy optionally include, but are notlimited to, one or more measurements of one or more wavelengths of theelectromagnetic energy and/or measurements of an extended-spectrum ofthe electromagnetic energy. One or more measurements of electromagneticenergy optionally include, but are not limited to, measurements over acumulative time interval and/or time dependent electromagnetic energymeasurements. One or more time dependent measurements may include, butare not limited to, measurements at one or more times and/ormeasurements at one or more time intervals following excitation of afluorescent response. One or more measurements of electromagnetic energyoptionally include, but are not limited to, one or more measurements ofthe location of the source and/or incidence of electromagnetic energy(e.g. a fluorescent response, excitation energy 116, ablation energy117, and/or targeting energy 118). One or more measurements of thelocation of the source and/or incidence of electromagnetic energyinclude, but are not limited to, one or more measurements of a directionof incidence electromagnetic energy, and/or one or more measurements ofa tissue depth of incidence electromagnetic energy. One or moremeasurements of electromagnetic energy optionally include, but are notlimited to, one or more measurements of a strength of theelectromagnetic energy.

In illustrative embodiments, a first input includes dara representativeof one or more characteristics of one or more targets and/or one or morediseases and/or disorders. In illustrative embodiments, a first inputincludes data representative of the target fluorescent response. Datarepresentative of the target fluorescent response may include, but isnot limited to, one or more measurements of electromagnetic energy,and/or one or more measurements of one or more temporal-spatiallocations of the target fluorescent response. As used herein, the term“temporal-spatial locations” may include one or more temporal locationsand/or one or more spatial locations. Data representative of a targetfluorescent response may include, but is not limited to, a clustering offluorescent responses that would otherwise be considered a normalresponse in the absence of clustering, or with limited clustering, ornon-significant clustering. In illustrative embodiments, clusteringmight include cells forming a plaque, bacterial cells forming a colony,blood cells forming a clot, malaria-infected red blood cellsaggregating, among others.

In illustrative embodiments, a first possible dataset includes datarepresentative of one or more fluorescence characteristics of one ormore possible constituents of the target area. As used herein, the term“constituents” may include, but is not limited to, cells, tissues,lumen, proteins, plaques, membranes, pathogens, microorganisms, and/orparasites, among others.

In illustrative embodiments, a first possible dataset includes datarepresentative of one or more numerical measurements for one or morepossible constituents of the target area. One or more numericalmeasurements may include, but are not limited to, one or more numericalmeasurements for normal levels of one or more possible constituents ofthe target area and/or for abnormal levels of one or more possibleconstituents of the target area.

In illustrative embodiments, a first possible dataset includes datarepresentative of excitation energy 116. Data representative ofexcitation energy 116 includes, but is not limited to, datarepresentative of one or more characteristics of excitation energy 116.Data representative of one or more characteristics of excitation energy116 include, but are not limited to, strength of the excitation energy,one or more wavelengths of the excitation energy, one or more spatialparameters of the excitation energy, and/or one or more directionalparameters of the excitation energy. One or more spatial parameters ofthe excitation energy include, but are not limited to, one or morespatial limitations of the excitation energy, optionally including, butnot limited to, spatially focused and spatially collimated. One or moredirectional parameters of the excitation energy include, but are notlimited to, directionally limited, directionally varied anddirectionally variable.

One or more characteristics of the excitation energy include, but arenot limited to, manual, programmable, automatic, remote-controlled, andfeedback-control. In illustrative embodiments, for example, subsequentexcitation energy characteristics may be determined based on one or morecharacteristics of the fluorescent emissions associated with thecharacteristics of the previous excitation energy selected. For example,if the previous excitation energy induced a fluorescent response withhigh background and/or non-specific emissions, or without a targetsignal, a different excitation energy might be selected. In illustrativeembodiments, for example, excitation energy may be at least partiallydetermined by the location, and/or as a result of a prior ablation.

In illustrative embodiments, a first possible dataset includes datarepresentative of ablation energy 117. Data representative of ablationenergy 117 optionally includes, but is not limited to datarepresentative of one or more characteristics of the ablation energy117. One or more characteristics of the ablation energy include, but arenot limited to, strength of the ablation energy, one or more wavelengthsof the ablation energy, one or more spatial parameters of the ablationenergy, and/or one or more directional parameters of the ablationenergy. One or more spatial parameters of the ablation energy include,but are not limited to, one or more spatial limitations of the ablationenergy, optionally including, but not limited to, spatially focused andspatially collimated. One or more directional parameters of the ablationenergy include, but are not limited to, directionally limited,directionally varied and directionally variable.

One or more characteristics of the ablation energy include, but are notlimited to, manual, programmable, automatic, remote-controlled, andfeedback-controlled. One or more characteristics of the ablation energyinclude, but are not limited to, the minimum energy associated with atleast partially ablating one or more target areas and/or one or morenon-target areas. One or more characteristics of the ablation energyinclude, but are not limited to, the one or more characteristics of theoptimum energy associated with at least partially ablating one or moretarget areas while minimizing and/or reducing the ablation of one ormore non-target areas (e.g. reducing collateral damage). In illustrativeembodiments, one or more characteristics of ablation energy may bedetermined based on detection of only partial ablation from a priorablation.

In some embodiments, ablation energy 117 is one or more of chargedparticles (e.g. from a particle beam) 112 or electromagnetic energy 111.In some embodiments, particle beam energy 112 may include, but is notlimited to, electrons, protons, alpha particles, beta particles and/orgamma particles. In some embodiments, electromagnetic energy 111 mayinclude, but is not limited to, optical energy 113 and/or X-ray 115energy. In some embodiments, ablation energy 117 is pulsed energy.

In illustrative embodiments of a receiving operation 160, 170, and/or180, receiving a first input associated with a first possible datasetincludes, but is not limited to, receiving a first data entry associatedwith the first possible dataset. In illustrative embodiments, a firstdata entry may include, but is not limited to, one or more measurementsof energy (optionally electromagnetic energy) and/or one or moremeasurements of one or more temporal-spatial locations of a fluorescentresponse (e.g. a target fluorescent response). In illustrativeembodiments, a first data entry may include, but is not limited to, datarepresentative of one or more characteristics of one or more targets,one or more diseases, and/or one or more disorders.

In illustrative embodiments of a receiving operation 160, 170, and/or180, receiving a first input associated with a first possible datasetincludes, but is not limited to, receiving a first data entry from asensor, from a database, and/or from a user interface (e.g. from atleast one submission element of a graphical user interface).

In illustrative embodiments of a receiving operation 160, 170, and/or180, receiving a first input associated with a first possible datasetincludes, but is not limited to, receiving a first data entry at leastpartially identifying one or more elements of the first possibledataset. In illustrative embodiments, one or more elements of the firstpossible dataset include one or more of one or more measurements ofelectromagnetic energy, one or more measurements of one or moretemporal-spatial locations of a target fluorescent response, datarepresentative of excitation energy, and/or data representative ofablation energy 117.

In illustrative embodiments of a receiving operation 160, 170, and/or180, receiving a first input associated with a first possible datasetincludes, but is not limited to, receiving a first request associatedwith the first possible dataset. In illustrative embodiments, the firstrequest includes, but is not limited to, selecting and/or determiningdata representative of one or more measurements of electromagneticenergy, data representative of one or more measurements of one or moretemporal-spatial locations of the target fluorescent response, and/ordata representative of one or more characteristics of ablation energy.

In illustrative embodiments of a receiving operation 160, 170, and/or180, receiving a first input associated with a first possible datasetincludes, but is not limited to, receiving a first request from a userinterface (e.g. at least one submission element of a graphical userinterface). In illustrative embodiments, the first request at leastpartially identifies and/or selects one or more elements of the firstpossible dataset. In illustrative embodiments, the first requestprovides instructions identifying, specifying, and/or determining datarepresentative of one or more elements of the first possible dataset.

In illustrative embodiments of an optional accessing operation 260, 270,and/or 280 accessing the first possible dataset in response to the firstinput includes, but is not limited to, accessing the first possibledataset using a database management system engine. In some embodiments,the database management system engine is configured to query a firstdatabase to retrieve the first possible dataset therefrom. Inillustrative embodiments, accessing the first possible dataset inresponse to the first input includes, but is not limited to, accessingthe first possible dataset by querying a first database to retrieve datarepresentative of one or more characteristics of one or more targetsassociated with one or more diseases and/or disorders.

In illustrative embodiments of an optional accessing operation 260, 270,and/or 280 accessing the first possible dataset in response to the firstinput includes, but is not limited to, accessing the first possibledataset from within a first database associated with a plurality ofmeasurements of electromagnetic energy, a plurality of measurements ofone or more temporal-spatial locations of the target fluorescentresponse, and/or a plurality of characteristics of ablation energy.

In illustrative embodiments of an optional accessing operation 260, 270,and/or 280 accessing the first possible dataset in response to the firstinput includes, but is not limited to, accessing the first possibledataset by associating data representative of one or more measurementsof electromagnetic energy, data representative of one or moretemporal-spatial locations of the target fluorescent response, and/ordata representative of one or more characteristics of ablation energywith one or more elements of the first possible dataset.

In illustrative embodiments of an accessing operation 260, 270, and/or280 accessing the first possible dataset in response to the first inputincludes, but is not limited to, accessing the first possible dataset bycorresponding data representative of one or more measurements ofelectromagnetic energy, data representative of one or moretemporal-spatial locations of the target fluorescent response, and/ordata representative of one or more characteristics of ablation energywith one or more elements of the first possible dataset.

In illustrative embodiments of an accessing operation 260, 270, and/or280 accessing the first possible dataset in response to the first inputincludes, but is not limited to, accessing the first possible dataset asbeing associated with data representative one or more measurements ofelectromagnetic energy, data representative of one or more measurementsof one or more temporal-spatial locations of the target fluorescentresponse, and/or data representative of one or more characteristics ofablation energy.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, generating the firstpossible dataset using a database management system engine. Inillustrative embodiments, generating the first possible dataset inresponse to the first input includes, but is not limited to, generatingthe first possible dataset using a database management system engine toretrieve data representative of one or more characteristics of one ormore targets associated with one or more diseases and/or disorders.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, generating the firstpossible dataset by corresponding and/or associating data representativeof one or more measurements of electromagnetic energy, datarepresentative of one or more measurements of temporal-spatial locationsof the target fluorescent response, and/or data representative of one ormore characteristics of ablation energy with one or more elements of thefirst possible dataset.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, receiving a firstrequest associated with the first possible dataset; and generating thefirst possible dataset in response to the first request, the firstrequest specifying data representative of one or more measurements ofelectromagnetic energy, data representative of one or more measurementsof one or more temporal-spatial locations of the target fluorescentresponse and/or data representative of one or more characteristics ofablation energy. In illustrative embodiments, the first requestspecifies one or more characteristics of one or more targets.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, receiving a firstrequest, the first request specifying data representative of one or moremeasurements of electromagnetic energy; and generating the firstpossible dataset in response to the first request at least partially byperforming an analysis of data representative of one or moremeasurements of one or more temporal-spatial locations of the targetfluorescent response.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, receiving a firstrequest, the first request specifying data representative of one or moremeasurements of one or more temporal-spatial locations of the targetfluorescent response; and generating the first possible dataset inresponse to the first request at least partially by performing ananalysis of data representative of one or more measurements ofelectromagnetic energy.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, receiving a firstrequest, the first request specifying data representative of one or morecharacteristics of ablation energy; and generating the first possibledataset in response to the first request at least partially byperforming an analysis of data representative of one or moremeasurements of electromagnetic energy.

In illustrative embodiments of an optional generating operation 360,370, and/or 380, generating the first possible dataset in response tothe first input includes, but is not limited to, receiving a firstrequest, the first request specifying data representative of one or morecharacteristics of ablation energy; and generating the first possibledataset in response to the first request at least partially byperforming an analysis of data representative one or more measurementsof one or more temporal-spatial locations of the target fluorescentresponse.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, determining thegraphical illustration of the first possible dataset for inclusion in adisplay element of a graphical user interface. In illustrativeembodiments, determining a graphical illustration of the first possibledataset includes, but is not limited to, determining a graphicalillustration of data representative of one or more characteristics ofone or more targets associated with one or more diseases and/ordisorders.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, performing an analysisof one or more elements of the first possible dataset to determine thelocation of the target area; and determining the graphical illustrationbased on the analysis.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, performing an analysisof one or more elements of the first possible dataset to determine thelocation of the target area; and determining the graphical illustrationincluding data representative of one or more measurements ofelectromagnetic energy, data representative of one or more measurementsof one or more temporal-spatial locations of the target fluorescentresponse, and/or data representative of one or more characteristics ofablation energy in association with a visual indicator related to thelocation of the target area.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, performing an analysisof one or more elements of the first possible dataset to determine afirst possible outcome; and determining the graphical illustration basedon the analysis. In illustrative embodiments, the first possible outcomeoptionally includes, but is not limited to, one or more of a possiblerisk, a possible result, or a possible consequence.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, performing an analysisof one or more elements of the first possible dataset to determine afirst possible outcome; and determining the graphical illustrationincluding data representative of one or more measurements ofelectromagnetic energy, data representative of one or more measurementsof one or more temporal-spatial locations of the target fluorescentresponse, and/or data representative of one or more characteristics ofablation energy in association with a visual indicator related to thefirst possible outcome.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, determining acorrelation between a first possible outcome and a type orcharacteristic of a visual indicator used in the graphical illustrationto represent the first possible outcome.

In illustrative embodiments of an optional determining operation 460,470, and/or 480, determining a graphical illustration of the firstpossible dataset includes, but is not limited to, determining thegraphical illustration of a first possible outcome based on use ofablation energy having one or more characteristics. A first possibleoutcome may include, but is not limited to, partial ablation, completeablation, non-target partial ablation, and/or non-target completeablation, among others.

In illustrative embodiments of a determining operation 570 and/or 580,determining data representative of a location of a target area at leastpartially based on the first possible dataset includes, but is notlimited to, determining data representative of the location of thetarget area at least partially based on the first possible dataset, thefirst possible dataset including one or more measurements ofelectromagnetic energy, and/or one or more measurements of the targetfluorescent response. In illustrative embodiments, determining datarepresentative of a location of a target area at least partially basedon the first possible dataset includes, but is not limited to,determining data representative of one or more characteristics of one ormore targets associated with one or more diseases and/or disorders.

In illustrative embodiments of a determining operation 570 and/or 580,determining data representative of a location of a target area at leastpartially based on the first possible dataset includes, but is notlimited to, performing an analysis of one or more elements of the firstpossible dataset; and determining data representative of the location ofthe target area at least partially based on the analysis. Inillustrative embodiments, analysis of the first possible dataset myinclude a determination of coordinates for ablation, and/or adetermination that one or more target locations are not within range ofablation energy, and/or a determination that ablation of one or moretargets has a possibility of causing non-target damage.

In illustrative embodiments of a determining operation 570 and/or 580,determining data representative of a location of a target area at leastpartially based on the first possible dataset includes, but is notlimited to, performing an analysis of one or more elements of the firstpossible dataset and at least one additional instruction; anddetermining data representative of the location of the target area atleast partially based on the analysis.

In illustrative embodiments of an optional generating operation 680,generating the first possible output in response to the first inputincludes, but is not limited to, generating the first possible output atleast partially based on information associated with the location of atarget and movement of an untethered device associated with ablation. Inillustrative embodiments, one or more target is identified, optionallyin a location too distant and/or obstructed for ablation and one or moreparameters associated with movement of the untethered device to alocation optionally to facilitate ablation are generated. Inillustrative embodiments, no targets are identified in a particularlocation and one or more parameters associated with movement of theuntethered device to another location optionally to facilitate furtherscreening are generated.

In illustrative embodiments of an optional sending operation 560, 670,and/or 780, sending a first output associated with the first possibledataset includes, but is not limited to, sending a first output to oneor more of a motive source 150, a power source 140, and/or an energysource 110, optionally an excitation energy source 116 and/or anablation energy source 117. In some embodiments, sending a first outputassociated with the first possible dataset includes, but is not limitedto, sending a first output to one or more external sources, optionallyto one or more control circuitry 130, optionally in an external and/orremote location, that optionally provide a graphical illustration of theoutput, and/or that provide analysis and feedback at least partiallybased on the output.

In illustrative embodiments of an optional determining operation 660,770, and/or 880, determining data representative of one or morecharacteristics of excitation energy 116 for inducing the targetfluorescent response includes, but is not limited to, determining one ormore characteristics of excitation energy 116 based at least partiallyon one or more of, but not limited to, the location of the lesion, thelumen, and/or the internal location, the environmental characteristicsof the location, the distance, depth of tissue, and putative target, aswell as the characteristics of the expected surrounding constituents.

In illustrative embodiments, one or more characteristics of theexcitation energy 116 include, but are not limited to, one or more ofstrength of the excitation energy, wavelengths of the excitation energy,spatial parameters of the excitation energy, and/or directionalparameters of the excitation energy. In some embodiments, one or morespatial parameters of the excitation energy include, but are not limitedto, one or more spatial limitations of the excitation energy and/or adepth of focus of the excitation energy. In some embodiments, one ormore spatial limitations include, but are not limited to, spatiallyfocused and spatially collimated. In some embodiments, one or morecharacteristics of the depth of focus of the excitation energy includes,but are not limited to, a depth of focus is below a surface of a lesion,beyond a surface of a wall of a lumen, and/or beyond a surface of aninternal location. In illustrative embodiments, a depth of focus isapproximately 0.1 mm to 3 mm below a surface of a lesion, beyond asurface of a wall of a lumen, and/or beyond a surface of an internallocation. In some embodiments, one or more directional parametersinclude, but are not limited to, directionally limited, directionallyvaried and directionally variable.

In illustrative embodiments, one or more characteristics of theexcitation energy 116 include, but are not limited to, manual,programmable, automatic, remote-controlled, and feedback-controlled. Inillustrative embodiments, a care-giver (physician, veterinarian,dentist, etc.) makes the final determination for ablation based oninformation determined by one or more program, and manually releases theprogrammably determined ablation energy.

In illustrative embodiments, excitation energy 116 is electromagneticenergy, optionally optical energy. In illustrative embodiments,excitation energy 116 is pulsed energy. In illustrative embodiments,excitation energy 116 is optionally single photon electromagneticenergy, two photon electromagnetic energy, multiple wavelengthelectromagnetic energy, and/or extended-spectrum electromagnetic energy.In some embodiments, two photon electromagnetic energy is coupledthrough a virtual energy level and/or through an intermediate energylevel. In some embodiments, two photon electromagnetic energy isgenerated by two photons having the same wavelength or by two photonshaving a different wavelength.

In Illustrative embodiments of an optional determining operation 760,870, and/or 980, determining data representative of one or morecharacteristics of ablation energy for at least partially ablating thetarget area includes, but is not limited to, assessing one or morecharacteristics of one or more constituents, assessing one or morecharacteristics of the target (e.g. location, size, depth, distance,etc.), and/or selecting one or more energy sources. In illustrativeembodiments, the one or more characteristics of the ablation energy areselected to optimally ablate the target area while minimizing ablationoutside the target area.

In illustrative embodiments, optional receiving and determiningoperations 860 and/or 970 include receiving a second input associatedwith a second possible dataset, the second possible dataset includingdata representative of a second target fluorescent response following atleast partial ablation of the target area; and determining datarepresentative of one or more characteristics of ablation energy forfurther ablating the target area at least partially based on the secondpossible dataset. In illustrative embodiments, excitation energy isoptionally provided following at least partial ablation of one or moretarget optionally to determine the extent of ablation of target and/ornon-target tissues and/or cells. Emission information detected by one ormore sensor is optionally used to determine locations (optionallycoordinates) for additional ablation, as necessary.

In illustrative embodiments, optional receiving and determiningoperations 960 and/or 1070 include receiving a third input associatedwith a third possible dataset, the third possible dataset including datarepresentative of a fluorescent response; and determining datarepresentative of one or more characteristics of excitation energy forinducing the target fluorescent response at least partially based on thethird possible dataset. In illustrative embodiments, excitation energyof one or more characteristics may not elicit an identifiable and/ordetectable target fluorescent response by the sensor. At least partiallybased on the lack of detection of a target fluorescent response (and thecharacteristics of the excitation energy released), characteristics ofan additional excitation energy for release are selected, and optionallyprovided to the electromagnetic energy source 111, optionally one ormore excitation energy source 116.

In illustrative embodiments of a providing operation 1060 and/or 1170,providing a first output to a first energy source in real time includes,but is not limited to, sending the first output to the first energysource in real time.

In illustrative embodiments of a providing operation 1060 and/or 1170,providing a first output to a first energy source in real time includes,but is not limited to, sending a first instruction associated with thefirst possible dataset to the first energy source. In illustrativeembodiments, the first instruction contains data representative of oneor more measurements of electromagnetic energy, data representative ofone or more measurements of target fluorescent energy, datarepresentative of one or more characteristics of ablation energy, datarepresentative of one or more characteristics of targeting energy,and/or data representative of the location of the target area to be atleast partially ablated.

In illustrative embodiments of a providing operation 1060 and/or 1170,providing a first output to a first energy source in real time includes,but is not limited to, sending the first output to the first targetingenergy source in real time, the first output providing datarepresentative of the one or more ablation characteristics for at leastpartially ablating the target area.

In illustrative embodiments, a first energy source 110 is anelectromagnetic energy source 111, optionally an optical energy source113 and/or an X-ray energy source 115. In some embodiments, the firstenergy source 110 is a laser. In illustrative embodiments, a firstenergy source 110 is a charged particle source 112 that optionallyprovides particles including, but not limited to, electrons, protons,alpha particles, beta particles, and/or gamma particles.

In illustrative embodiments, a first output includes data representativeof one or more characteristics of ablation energy 117 for at leastpartially ablating the target area. In illustrative embodiments,ablation energy 117 is electromagnetic energy and/or charged particles.In illustrative embodiments, a first output includes targeting data forat least partially ablating the target area. In illustrativeembodiments, a first output includes data representative of the locationof the target area to be at least partially ablated.

In illustrative embodiments, a first targeting energy 118 has adifferent spatial irradiation extent than the first energy source 110.in some embodiments, the first targeting energy source provideselectromagnetic targeting energy, optionally optical targeting energy,optionally visual targeting energy.

In illustrative embodiments of a providing operation 1080, providing afirst output to a first motive source includes, but is not limited to,providing a first output to a first motive source in real time. Inillustrative embodiments of a providing operation 1080, providing afirst output to a first motive source includes, but is not limited to,sending the first output to the first motive source optionally in realtime.

The following provides a description of illustrative computer programproducts 1200, 1300, and/or 1400 based on one or more of the operationalflows 600, 700, and/or 800 and variations thereof as described above.These computer program products may also be executed in a variety ofother contexts and environments, and or in modified versions of thosedescribed herein. In addition, although some of the computer programproducts are presented in sequence, the various instructions may beperformed in various repetitions, concurrently, and/or in other ordersthan those that are illustrated. Although instructions for severalcomputer program products are described separately herein, theseinstructions may be performed in sequence, in various repetitions,concurrently, and in a variety of orders not specifically illustratedherein. In addition, one or more of the instructions described for oneor more computer program products may be added to another computerprogram product and/or used to replace one or more instructions in thecomputer program products, with or without deletion of one or moreinstructions of the computer program products.

FIG. 14 and FIG. 15 show a schematic of a partial view of anillustrative computer program product 1200 that includes a computerprogram for executing a computer process on a computing device. Anillustrative embodiment of the illustrative computer program product isprovided using a signal bearing medium 1210, and may include at leastone of one or more instructions 1215 including: one or more instructionsfor receiving a first input associated with a first possible dataset,the first possible dataset including data representative of a targetfluorescent response; one or more instructions for accessing the firstpossible dataset in response to the first input; one or moreinstructions for generating the first possible dataset in response tothe first input; one or more instructions for determining a graphicalillustration of the first possible dataset; one or more instructions forsending the first output associated with the first possible dataset; oneor more instructions for determining data representative of one or morecharacteristics of excitation energy for inducing the target fluorescentresponse; one or more instructions for determining data representativeof one or more characteristics of ablation energy for at least partiallyablating a target; one or more instructions for receiving a second inputassociated with a second possible dataset, the second possible datasetincluding data representative of a second target fluorescent responsefollowing at least partial ablation of a target; one or moreinstructions for determining data representative of one or morecharacteristics of ablation energy for further ablating a target atleast partially based on the second possible dataset; one or moreinstructions for receiving a third input associated with a thirdpossible dataset, the third possible dataset including datarepresentative of a fluorescent response; one or more instructions fordetermining data representative of one or more characteristics ofexcitation energy for inducing the target fluorescent response at leastpartially based on the third possible dataset; one or more instructionsfor providing a first output to a first energy source in real time, thefirst output providing data associated with at least partial ablation ofa target at least partially based on the first possible dataset. The oneor more instructions may be, for example, computer executable and/orlogic implemented instructions. In some embodiments, the signal bearingmedium 1210 of the one or more computer program products 1200 include acomputer-readable medium 1220, a recordable medium 1230, and/or acommunications medium 1240.

FIG. 16 and FIG. 17 show a schematic of a partial view of anillustrative computer program product 1300 that includes a computerprogram for executing a computer process on a computing device. Anillustrative embodiment of the illustrative computer program product isprovided using a signal bearing medium 1310, and may include at leastone of one or more instructions 1315 including: one or more instructionsfor receiving a first input associated with a first possible dataset,the first possible dataset including data representative of a targetfluorescent response; one or more instructions for accessing the firstpossible dataset in response to the first input; one or moreinstructions for generating the first possible dataset in response tothe first input; one or more instructions for determining a graphicalillustration of the first possible dataset; one or more instructions fordetermining data representative of a location of a target area at leastpartially based on the first possible dataset; one or more instructionsfor sending the first output associated with the first possible dataset;one or more instructions for determining data representative of one ormore characteristics of excitation energy for inducing the targetfluorescent response; one or more instructions for determining datarepresentative of one or more characteristics of ablation energy for atleast partially ablating a target; one or more instructions forreceiving a second input associated with a second possible dataset, thesecond possible dataset including data representative of a second targetfluorescent response following at least partial ablation of a target;one or more instructions for determining data representative of one ormore characteristics of ablation energy for further ablating a target atleast partially based on the second possible dataset; one or moreinstructions for receiving a third input associated with a thirdpossible dataset, the third possible dataset including datarepresentative of a fluorescent response; one or more instructions fordetermining data representative of one or more characteristics ofexcitation energy for inducing the target fluorescent response at leastpartially based on the third possible dataset; one or more instructionsfor providing a first output to a first energy source in real time, thefirst output providing data representative of one or more ablationcharacteristics for at least partially ablating the target area. The oneor more instructions may be, for example, computer executable and/orlogic implemented instructions. In some embodiments, the signal bearingmedium 1310 of the one or more computer program products 1300 include acomputer-readable medium 1320, a recordable medium 1330, and/or acommunications medium 1340.

FIG. 18 and FIG. 19 show a schematic of a partial view of anillustrative computer program product 1400 that includes a computerprogram for executing a computer process on a computing device. Anillustrative embodiment of the illustrative computer program product isprovided using a signal bearing medium 1410, and may include at leastone of one or more instructions 1415 including: one or more instructionsfor receiving a first input associated with a first possible dataset,the first possible dataset including data representative of afluorescent response; one or more instructions for accessing the firstpossible dataset in response to the first input; one or moreinstructions for generating the first possible dataset in response tothe first input; one or more instructions for determining a graphicalillustration of the first possible dataset; one or more instructions fordetermining data representative of a location of a target area at leastpartially based on the first possible dataset; one or more instructionsfor generating the first possible output in response to the first input;one or more instructions for sending the first output associated withthe first possible dataset; one or more instructions for determiningdata representative of one or more characteristics of excitation energyfor inducing the target fluorescent response; one or more instructionsfor determining data representative of one or more characteristics ofablation energy for at least partially ablating a target; one or moreinstructions for providing a first possible output to a first motivesource, the first possible output providing data representative of oneor more parameters associated with movement of an untethered device in alumen at least partially based on the location of the target area. Theone or more instructions may be, for example, computer executable and/orlogic implemented instructions. In some embodiments, the signal bearingmedium 1410 of the one or more computer program products 1400 include acomputer-readable medium 1420, a recordable medium 1430, and/or acommunications medium 1440.

The following provides a description of illustrative systems based onone or more of the operational flows 600, 700, and/or 800 and/orcomputer program products 1200, 1300, and/or 1400 and/or variationsthereof as described above. These systems may also be executed in avariety of other contexts and environments, and or in modified versionsof those described herein.

FIG. 20 and FIG. 21 show a schematic of an illustrative system 1500 inwhich embodiments may be implemented. In some embodiments, system 1500may be the same as system 1600 and/or system 1700. In some embodiments,system 1500 may be different from system 1600 and/or system 1700. System1500 may include a computing system environment 1510. System 1500 alsoillustrates an operator 1501 (e.g. a medical or veterinary professional,optionally a surgeon, a veterinarian, a nurse, a technician, etc.) usinga device 1540 that is optionally shown as being in communication with acomputing device 1520 by way of an optional coupling 1545. The optionalcoupling may represent a local, wide area, or peer-to-peer network, ormay represent a bus that is internal to a computing device (e.g. inillustrative embodiments the computing device 1520 is contained in wholeor in part within the device 1510, 1540, 200, 300, and/or 400 or withinone or more apparatus 100 and/or 500, or one or more control circuitry130). An optional storage medium 1525 may be any computer storagemedium.

The computing device 1520 includes one or more computer executableinstructions 1530 that when executed on the computing device 1520 causethe computing device 1520 receive a first input associated with a firstpossible dataset, the first possible dataset including datarepresentative of a target fluorescent response; access the firstpossible dataset in response to the first input; generate the firstpossible dataset in response to the first input; determine a graphicalillustration of the first possible dataset; send the first outputassociated with the first possible dataset; determine datarepresentative of one or more characteristics of excitation energy forinducing the target fluorescent response; determine data representativeof one or more characteristics of ablation energy for at least partiallyablating a target; receive a second input associated with a secondpossible dataset, the second possible dataset including datarepresentative of a second target fluorescent response following atleast partial ablation of a target; determine data representative of oneor more characteristics of ablation energy for further ablating a targetat least partially based on the second possible dataset; receive a thirdinput associated with a third possible dataset, the third possibledataset including data representative of a fluorescent response;determine data representative of one or more characteristics ofexcitation energy for inducing the target fluorescent response at leastpartially based on the third possible dataset; provide a first output toa first energy source in real time, the first output providing dataassociated with at least partial ablation of a target at least partiallybased on the first possible dataset. In some illustrative embodiments,the computing device 1520 may optionally be contained in whole or inpart within one or more parts of an apparatus 100 and/or 500 and/or oneor more devices 200, 300, and/or 400 (e.g. control circuitry 130 of oneor more tethered and/or untethered, internal and/or external, movableand/or fixed apparatus and/or device), or may optionally be contained inwhole or in part within the operator device 1540.

The system 1500 includes at least one computing device 1510, 1520, 1540and/or control circuitry 130 on which the computer-executableinstructions 1530 may be executed. For example, one or more of thecomputing devices 1510, 1520, 1540 and/or control circuitry 130 mayexecute the one or more computer executable instructions 1530 and outputa result and/or receive information from the operator 1501, from otherexternal sources, and/or from one or more sensor 120, on the same or adifferent computing device 1510, 1520, 1540, 1610, 1620, 1640, 1710,1720, and/or 1740 and/or output a result and/or receive information fromone or more apparatus 100 and/or 500 and/or one or more device 200, 300and/or 400 in order to perform and/or implement one or more of thetechniques, processes, or methods described herein, and/or othertechniques.

The computing device 1510, 1520, and/or 1540 may include one or more ofa desktop computer, a workstation computer, a computing system compriseda cluster of processors, a networked computer, a tablet personalcomputer, a laptop computer, or a personal digital assistant, or anyother suitable computing unit. In some embodiments, any one of the oneor more computing devices 1510, 1520, and/or 1540 and/or controlcircuitry 130 may be operable to communicate with a database to accessthe first possible dataset and/or subsequent datasets. In someembodiments, the computing device 1510, 1520, and/or 1540 is operable tocommunicate with the one or more apparatus 100 and/or 500 and/or device200, 300, and/or 400 (e.g. control circuitry 130).

FIG. 22 and FIG. 23 show a schematic of an illustrative system 1600 inwhich embodiments may be implemented. In some embodiments, system 1600may be the same as system 1500 and/or system 1700. In some embodiments,system 1600 may be different from system 1500 and/or system 1700. System1600 may include a computing system environment 1510. System 1600 alsoillustrates an operator 1501 (e.g. a medical or veterinary professional,optionally a surgeon, a veterinarian, a nurse, a technician, etc.) usinga device 1540 that is optionally shown as being in communication with acomputing device 1620 by way of an optional coupling 1545. An optionalstorage medium 1525 may be any computer storage medium.

The computing device 1620 includes one or more computer executableinstructions 1630 that when executed on the computing device 1620 causethe computing device 1620 to receive a first input associated with afirst possible dataset, the first possible dataset including datarepresentative of a target fluorescent response; access the firstpossible dataset in response to the first input; generate the firstpossible dataset in response to the first input; determine a graphicalillustration of the first possible dataset; determine datarepresentative of a location of a target area at least partially basedon the first possible dataset; send the first output associated with thefirst possible dataset; determine data representative of one or morecharacteristics of excitation energy for inducing the target fluorescentresponse; determine data representative of one or more characteristicsof ablation energy for at least partially ablating a target; receive asecond input associated with a second possible dataset, the secondpossible dataset including data representative of a second targetfluorescent response following at least partial ablation of a target;determine data representative of one or more characteristics of ablationenergy for further ablating a target at least partially based on thesecond possible dataset; receive a third input associated with a thirdpossible dataset, the third possible dataset including datarepresentative of a fluorescent response; determine data representativeof one or more characteristics of excitation energy for inducing thetarget fluorescent response at least partially based on the thirdpossible dataset; provide a first output to a first energy source inreal time, the first output providing data representative of one or moreablation characteristics for at least partially ablating the targetarea.

In some illustrative embodiments, the computing device 1620 mayoptionally be contained in whole or in part within one or more parts ofan apparatus 100 and/or 500 and/or one or more devices 200, 300, and/or400 (e.g. control circuitry 130 of one or more tethered and/oruntethered, internal and/or external, movable and/or fixed apparatusand/or device), or may optionally be contained in whole or in partwithin the operator device 1540.

The system 1600 includes at least one computing device 1510, 1620, 1540and/or control circuitry 130 on which the computer-executableinstructions 1630 may be executed. For example, one or more of thecomputing devices 1510, 1620, 1540 and/or control circuitry 130 mayexecute the one or more computer executable instructions 1630 and outputa result and/or receive information from the operator 1501, from otherexternal sources, and/or from one or more sensor 120, on the same or adifferent computing device 1510, 1520, 1540, 1620, and/or 1720 and/oroutput a result and/or receive information from one or more apparatus100 and/or 500 and/or one or more device 200, 300 and/or 400 in order toperform and/or implement one or more of the techniques, processes, ormethods described herein, and/or other techniques.

The computing device 1510, 1620, 1540 may include one or more of adesktop computer, a workstation computer, a computing system comprised acluster of processors, a networked computer, a tablet personal computer,a laptop computer, or a personal digital assistant, or any othersuitable computing unit. In some embodiments, any one of the one or morecomputing devices 1510, 1620, and/or 1540 and/or control circuitry 130may be operable to communicate with a database to access the firstpossible dataset and/or subsequent datasets. In some embodiments, thecomputing device 1510, 1620, and/or 1540 is operable to communicate withthe one or more apparatus 100 and/or 500 and/or device 200, 300, and/or400 (e.g. control circuitry 130).

FIG. 24 and FIG. 25 show a schematic of an illustrative system 1700 inwhich embodiments may be implemented. In some embodiments, system 1700may be the same as system 1500 and/or system 1600. In some embodiments,system 1700 may be different from system 1500 and/or system 1600. System1700 may include a computing system environment 1510. System 1700 alsoillustrates an operator 1501 (e.g. a medical or veterinary professional,optionally a surgeon, a veterinarian, a nurse, a technician, etc.) usinga device 1540 that is optionally shown as being in communication with acomputing device 1720 by way of an optional coupling 1545. An optionalstorage medium 1525 may be any computer storage medium.

The computing device 1720 includes one or more computer executableinstructions 1730 that when executed on the computing device 1720 causethe computing device 1720 receive a first input associated with a firstpossible dataset, the first possible dataset including datarepresentative of a fluorescent response; access the first possibledataset in response to the first input; generate the first possibledataset in response to the first input; determine a graphicalillustration of the first possible dataset; determine datarepresentative of a location of a target area at least partially basedon the first possible dataset; generate the first possible output inresponse to the first input; send the first output associated with thefirst possible dataset; determine data representative of one or morecharacteristics of excitation energy for inducing the target fluorescentresponse; determine data representative of one or more characteristicsof ablation energy for at least partially ablating a target; provide afirst possible output to a first motive source, the first possibleoutput providing data representative of one or more parametersassociated with movement of an untethered device in a lumen at leastpartially based on the location of the target area.

In some illustrative embodiments, the computing device 1720 mayoptionally be contained in whole or in part within one or more parts ofan apparatus 100 and/or 500 and/or one or more devices 200, 300, and/or400 (e.g. control circuitry 130 of one or more tethered and/oruntethered, internal and/or external, movable and/or fixed apparatusand/or device), or may optionally be contained in whole or in partwithin the operator device 1540.

The system 1700 includes at least one computing device 1510, 1720, 1540and/or control circuitry 130 on which the computer-executableinstructions 1730 may be executed. For example, one or more of thecomputing devices 1510, 1720, 1540 and/or control circuitry 130 mayexecute the one or more computer executable instructions 1730 and outputa result and/or receive information from the operator 1501, from otherexternal sources, and/or from one or more sensor 120, on the same or adifferent computing device 1510, 1520, 1540, 1620, and/or 1720 and/oroutput a result and/or receive information from one or more apparatus100 and/or 500 and/or one or more device 200, 300 and/or 400 in order toperform and/or implement one or more of the techniques, processes, ormethods described herein, and/or other techniques.

The computing device 1510, 1720, 1540 may include one or more of adesktop computer, a workstation computer, a computing system comprised acluster of processors, a networked computer, a tablet personal computer,a laptop computer, or a personal digital assistant, or any othersuitable computing unit. In some embodiments, any one of the one or morecomputing devices 1510, 1720, and/or 1540 and/or control circuitry 130may be operable to communicate with a database to access the firstpossible dataset and/or subsequent datasets. In some embodiments, thecomputing device 1510, 1720, and/or 1540 is operable to communicate withthe one or more apparatus 100 and/or 500 and/or device 200, 300, and/or400 (e.g. control circuitry 130).

There is little distinction left between hardware and softwareimplementations of aspects of systems; the use of hardware or softwareis generally (but not always, in that in certain contexts the choicebetween hardware and software can become significant) a design choicerepresenting cost vs. efficiency tradeoffs. There are various vehiclesby which processes and/or systems and/or other technologies describedherein can be effected (e.g., hardware, software, and/or firmware), andthat the preferred vehicle will vary with the context in which theprocesses and/or systems and/or other technologies are deployed. Forexample, if an implementer determines that speed and accuracy areparamount, the implementer may opt for a mainly hardware and/or firmwarevehicle; if flexibility is paramount, the implementer may opt for amainly software implementation; or, yet again alternatively, theimplementer may opt for some combination of hardware, software, and/orfirmware.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operationwithin such block diagrams, flowcharts, or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter described herein may beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, those skilled in the art willrecognize that some aspects of the embodiments disclosed herein, inwhole or in part, can be equivalently implemented in integratedcircuits, as one or more computer programs running on one or morecomputers (e.g., as one or more programs running on one or more computersystems), as one or more programs running on one or more processors(e.g., as one or more programs running on one or more microprocessors),as firmware, or as virtually any combination thereof, and that designingthe circuitry and/or writing the code for the software and or firmwarewould be well within the skill of one of skill in the art in light ofthis disclosure. In addition, those skilled in the art will appreciatethat the mechanisms of the subject matter described herein are capableof being distributed as a program product in a variety of forms, andthat an illustrative embodiment of the subject matter described hereinapplies regardless of the particular type of signal bearing medium usedto actually carry out the distribution. Examples of a signal bearingmedium include, but are not limited to, the following: a recordable typemedium such as a floppy disk, a hard disk drive, a Compact Disc (CD), aDigital Video Disk (DVD), a digital tape, a computer memory, etc.; and atransmission type medium such as a digital and/or an analogcommunication medium (e.g., a fiber optic cable, a waveguide, a wiredcommunications link, a wireless communication link, etc.).

Those skilled in the art will recognize that it is common within the artto describe devices and/or processes in the fashion set forth herein,and thereafter use engineering practices to integrate such describeddevices and/or processes into data processing systems. That is, at leasta portion of the devices and/or processes described herein can beintegrated into a data processing system via a reasonable amount ofexperimentation. Those having skill in the art will recognize that atypical data processing system generally includes one or more of asystem unit housing, a video display device, a memory such as volatileand non-volatile memory, processors such as microprocessors and digitalsignal processors, computational entities such as operating systems,drivers, graphical user interfaces, and applications programs, one ormore interaction devices, such as a touch pad or screen, and/or controlsystems including feedback loops and control motors (e.g., feedback forsensing position and/or velocity; control motors for moving and/oradjusting components and/or quantities). A typical data processingsystem may be implemented utilizing any suitable commercially availablecomponents, such as those typically found in datacomputing/communication and/or network computing/communication systems.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely exemplary, and that in fact many other architectures can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected”, or“operably coupled”, to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably couplable”, to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to physically mateable and/or physically interactingcomponents and/or wirelessly interactable and/or wirelessly interactingcomponents and/or logically interacting and/or logically interactablecomponents.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

For ease of reading, all values described herein, and all numericalranges described herein are approximate and should be read as includingthe word “about” or “approximately” prior to each numeral, unlesscontext indicates otherwise. For example, the range “0.0001 to 0.01” ismeant to read as “about 0.0001 to about 0.01.”

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood by those within the art that if aspecific number of an introduced claim recitation is intended, such anintent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All references, including but not limited to patents, patentapplications, and non-patent literature are hereby incorporated byreference herein in their entirety.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

1. A device for treating or ameliorating H. pylori infection comprising:an untethered ingestible mass having one or more optical energy sourceconfigured to emit variable directional electromagnetic energy in amanner selected to induce photodynamic cell death in H. pylori.
 2. Thedevice of claim 1, wherein the untethered ingestible mass is shaped forrandom movement.
 3. The device of claim 1, wherein the untetheredingestible mass is shaped for predictable movement.
 4. The device ofclaim 1, wherein the untethered ingestible mass is shaped for continualmovement.
 5. The device of claim 1, wherein the untethered ingestiblemass is cylindrical.
 6. The device of claim 1, wherein the untetheredingestible mass is a rotationally symmetrical body with an axialdimension greater than an equatorial dimension.
 7. The device of claim1, wherein the untethered ingestible mass is spherical.
 8. The device ofclaim 1, wherein the untethered ingestible mass is designed topredictably rotate.
 9. The device of claim 1, wherein the untetheredingestible mass is designed to continually rotate.
 10. The device ofclaim 1, wherein the untethered ingestible mass is designed to randomlyrotate.
 11. The device of claim 1, wherein the untethered ingestiblemass is designed to randomly tumble.
 12. The device of claim 1, whereinthe untethered ingestible mass is designed to randomly wobble.
 13. Thedevice of claim 1, further comprising: a motor coupled to a movablemass.
 14. The device of claim 13, wherein the movable mass is configuredto cause variable moments of inertia.
 15. The device of claim 13,wherein the movable mass is configured to undergo unbalanced rotation.16. The device of claim 13, wherein the movable mass is configured toundergo linear oscillatory motion.
 17. The device of claim 13, whereinthe movable mass is configured to undergo eccentric motion.
 18. Thedevice of claim 13, further comprising: a power source. 19-23.(canceled)
 24. The device of claim 18, further comprising: controlcircuitry coupled to the power source.
 25. The device of claim 24,wherein the control circuitry is configured to control the motor. 26.The device of claim 24, wherein the control circuitry is configured tocontrol the one or more optical energy source.
 27. The device of claim24, wherein the power source is connected to the motor.
 28. The deviceof claim 24, wherein the power source is connected to the one or moreoptical energy source. 29-33. (canceled)
 34. The device of claim 24,wherein the control circuitry is configured to be monitored by one ormore external sources.
 35. The device of claim 24, wherein the controlcircuitry is configured to provide one or more outputs to one or moreexternal sources.
 36. (canceled)
 37. The device of claim 24, furthercomprising: a sensor coupled to the control circuitry and configured todetect one or more environmental parameters. 38-45. (canceled)
 46. Thedevice of claim 1, wherein the one or more optical energy source isconfigured to emit the electromagnetic energy from one or morelocations.
 47. The device of claim 1, wherein the one or more opticalenergy source is configured to emit the electromagnetic energy in one ormore directions.
 48. The device of claim 1, wherein the one or moreoptical energy source is configured to continuously emit theelectromagnetic energy.
 49. The device of claim 1, wherein the one ormore optical energy source is configured to intermittently emit theelectromagnetic energy.
 50. The device of claim 1, wherein the one ormore optical energy source is configured to randomly emit theelectromagnetic energy.
 51. The device of claim 1, wherein the one ormore optical energy source is configured to emit the electromagneticenergy in a time-dependent manner.
 52. The device of claim 1, whereinthe one or more optical energy source is configured to emit theelectromagnetic energy in a spatially variable manner.
 53. The device ofclaim 1, wherein the one or more optical energy source is configuredemit the electromagnetic energy in a pH-dependent manner.
 54. The deviceof claim 1, wherein the one or more optical energy source is configuredemit the electromagnetic energy in an orientation-dependent manner. 55.The device of claim 1, wherein the one or more optical energy source isconfigured to emit the electromagnetic energy in a programmable manner.56. The device of claim 55, the one or more optical energy source isprogrammed to emit the electromagnetic energy in a time-dependentmanner.
 57. The device of claim 55, the one or more optical energysource is programmed to emit the electromagnetic energy in apH-dependent manner.
 58. The device of claim 1, wherein the emission ofthe electromagnetic energy is remote-controlled.
 59. The device of claim1, further comprising: control circuitry coupled to the optical energysource and configured to control the emission of the electromagneticenergy. 60-67. (canceled)
 68. The device of claim 59, furthercomprising: a sensor coupled to the control circuitry and configured todetect one or more environmental parameters. 69-70. (canceled)
 71. Adevice for ablating H. pylori comprising: an untethered ingestible massshaped for non-uniform movement having an optical energy sourceconfigured to emit electromagnetic energy in a manner selected to inducephotodynamic cell death in H. pylori.
 72. (canceled)
 73. A method fortreating or ameliorating H. pylori infection comprising: providing to adigestive tract of a subject an untethered ingestible mass; and emittingvariable directional electromagnetic energy from the untetheredingestible mass in a manner selected to induce photodynamic cell deathin H. pylori. 74-78. (canceled)
 79. The method of claim 73, wherein theuntethered ingestible mass comprises: a motor coupled to a movable mass.80. The method of claim 79, further comprising: inducing variablemoments of inertia by moving the movable mass.
 81. The method of claim79, further comprising: inducing the movable mass to undergo unbalancedrotation.
 82. The method of claim 79, further comprising: inducing themovable mass to undergo linear oscillatory movement.
 83. The method ofclaim 79, further comprising: inducing the movable mass to undergoeccentric movement.
 84. The method of claim 79, wherein the untetheredingestible mass includes a power source. 85-98. (canceled)
 99. Themethod of claim 73, further comprising: monitoring the untetheredingestible device from one or more external sources.
 100. The method ofclaim 73, further comprising: providing one or more outputs from theuntethered ingestible device to one or more external sources.
 101. Themethod of claim 73, further comprising: detecting one or moreenvironmental parameters. 102-119. (canceled)
 120. The method of claim73, wherein emitting variable directional electromagnetic energy fromthe untethered ingestible mass in a manner selected to inducephotodynamic cell death in H. pylori comprises: emitting the variabledirectional electromagnetic energy from the untethered ingestible massin a spatially variable manner.
 121. The method of claim 73, whereinemitting variable directional electromagnetic energy from the untetheredingestible mass in a manner selected to induce photodynamic cell deathin H. pylori comprises: emitting the variable directionalelectromagnetic energy from the untethered ingestible mass at one ormore intervals at least partially based on pH.
 122. The method of claim73, wherein emitting variable directional electromagnetic energy fromthe untethered ingestible mass in a manner selected to inducephotodynamic cell death in H. pylori comprises: emitting the variabledirectional electromagnetic energy from the untethered ingestible massat one or more intervals at least partially based on orientation.123-124. (canceled)
 125. The method of claim 73, further comprising:controlling the emission of the variable directional electromagneticenergy from the untethered ingestible mass using control circuitry. 126.The method of claim 125, further comprising: detecting one or moreenvironmental parameters using a sensor coupled to the controlcircuitry.
 127. The method of claim 126, further comprising: emittingthe variable directional electromagnetic energy from the untetheredingestible mass at least partially based on the one or moreenvironmental parameters. 128-129. (canceled)